6-, 7-, OR 8-SUBSTITUTED QUINAZOLINONE DERIVATIVES AND COMPOSITIONS COMPRISING THE SAME

DERIVES DE QUINAZOLINONE SUBSTITUEE EN 6-, 7- OU 8- ET COMPOSITIONS EN RENFERMANT

English Abstract

Provided are quinazolinone compounds, having a structure of formula (II):
(see formula II)
and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers,
and prodrugs
thereof. Pharmaceutical compositions of these compounds are disclosed.

French Abstract

La présente invention concerne des composés de quinazolinone, et leurs sels pharmaceutiquement acceptables, solvates, clathrates, stéréoisomères, et promédicaments. L'invention concerne également des procédés d'utilisation et des compositions pharmaceutiques de ces composés.

Claims

CLAIMS:
1. A compound having a structure of formula (II):
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R7 is: halo; -(CH2)OH; (C1-C6)alkyl, optionally substituted with one or
more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
-(CH2)n NHR d, wherein R d is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)n-(6 to 10 membered aryl);
-C(O)-(CH2)n-(6 to 10 membered aryl) or -C(O)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one
or more
of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with one or more
halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more halo;
-C(O)-(CH2)n-(C3-C10-cycloalkyl);
-C(O)-(CH2)n-NR e R f, wherein R e and R f are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
81

6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(CH2)n-O-(C1-C6)alkyl; or
-C(O)-(CH2)n-O-(CH2)n-(6 to 10 membered aryl);
R8 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R9 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
2. The compound of claim 1, having a structure of formula (III):
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R10 is: halo; -(CH2)n OH; (C1-C6)alkyl, optionally substituted with one or
more halo; or
(C1-C6)alkoxy, optionally substituted with one or more halo;
R11 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R12 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate,
or
stereoisomer thereof, wherein R10 is a halogen, methyl, or hydroxyl.
82

4. The compound of claim 2, or a pharmaceutically acceptable salt, solvate,
or
stereoisomer thereof, wherein R11 is hydrogen or methyl.
5. The compound of claim 2, or a pharmaceutically acceptable salt, solvate,
or
stereoisomer thereof, wherein R12 is hydrogen or methyl.
6. The compound of claim 2, which is:
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
7. The compound of claim 1 having a structure of formula (IV):
Image
or a pharmaceutically acceptable salt, solvate,-or stereoisomer thereof,
wherein:
R g is:
hydrogen;
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(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)n-(6 to 10 membered aryl);
-C(O)-(CH2)n-(6 to 10 membered aryl) or -C(O)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one
or more
of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with one or more
halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more halo;
-C(O)-(CH2)n-(C3-C10-cycloalkyl);
-C(O)-(CH2)n-NR h R i, wherein R h and R i are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(CH2)n-O-(C1-C6)alkyl; or
-C(O)-(CH2)n-O-(CH2)n-(6 to 10 membered aryl);
R13 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R14 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
8. The compound of claim 7, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R g is hydrogen.
84

9. The compound of claim 7, or a pharmaceutically acceptable salt, solvate,
or
stereoisomer thereof, wherein R g is -C(O)-(C1-C6)alkyl.
10. The compound of claim 7, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R g is -C(O)-phenyl, optionally substituted with
one or more of halo, and
(C1-C6)alkyl.
11. The compound of claim 7, which is:
Image

Image
or a pharmaceutically acceptable salt, solvate,-or stereoisomer thereof.
12. A compound having a structure of formula (V):
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R15 is: halo; -(CH2)n OH; (C1-C6)alkyl, optionally substituted with one or
more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
-(CH2)n NHR j, wherein R j is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)n-(6 to 10 membered aryl);
-C(O)-(CH2)-(6 to 10 membered aryl) or -C(O)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one
or more
of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with one or more
halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more
halo;
86

-C(O)-(CH2)n-(C1-C10-cycloalkyl);
-C(O)-(CH2)n-NR k R l, wherein R k and R I are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(CH2)n-O-(C1-C6)alkyl; or
-C(O)-(CH2)n-O-(CH)n-(6 to 10 membered aryl);
R16 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R17 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
13. The compound of claim 12, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R15 is a halogen or methyl.
14. The compound of claim 12, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R15 is -(CH2)n NHR j.
15. The compound of claim 14, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R j is hydrogen or -C(O)-O-(C1-C6)alkyl.
16. The compound of claim 12, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R16 is hydrogen or methyl.
87

1 7. The compound of claim 12, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R17 is hydrogen or methyl.
18. The compound of claim 12, which is:
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
19. A compound having a structure of formula (VI):
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R18 is: halo; -(CH2)OH; (C1-C6)alkyl, optionally substituted with one or
more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
88

-(CH2)n NHR m, wherein R m is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)n-(6 to 10 membered aryl);
-C(O)-(CH2)n-(6 to 10 membered aryl) or -C(O)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one
or more
of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with one or more
halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more halo;
-C(O)-(CH2)n-(C3-C10-cycloalkyl);
-C(O)-(CH2)n-NR n R o, wherein R n and R o are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(O)-(CH2)n-O-(C1-C6)alkyl; or
-C(O)-(CH2)n-O-(CH2)n-(6 to 10 membered aryl);
R19 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R20 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
89

n is 0, 1, or 2.
20. The compound of claim 19, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R18 is a halogen, methyl, hydroxyl, or -CF3.
21. The compound of claim 19, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R19 is hydrogen or methyl.
22. The compound of claim 19, or a pharmaceutically acceptable salt,
solvate, or
stereoisomer thereof, wherein R29 is hydrogen.
23. The compound of claim 19, which is:
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
24. A compound of formula (VII):

Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein:
R21 is hydrogen;
R22, R23, and R24 are each independently:
halo; -(CH2)n OH; (C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
two of R21-R24 together form a 5 to 6 membered ring, optionally substituted
with one
or more of: halo; (C1-C6)alkyl, optionally substituted with one or more halo;
and
(C1-C6)alkoxy, optionally substituted with one or more halo;
R25 is: hydrogen; -(CH2)n OH; phenyl; -O-(C1-C6)alkyl; or (C1-C6)alkyl,
optionally substituted
with one or more halo;
R26 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
25. A compound of formula:
Image
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
91

26. A pharmaceutical composition comprising a compound of any one of claims
1
to 25, or a pharmaceutically acceptable salt, solvate, or stereoisomer
thereof, and a
pharmaceutically acceptable excipient or carrier.
27. Use of a compound of any one of claims 1 to 25, or a pharmaceutically
acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical
composition of claim 26,
as a TNF.alpha. inhibitor.
92

Description

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6-4 7-, OR 8-SUBSTITUTED OUINAZOLINONE DERIVATIVES
AND COMPOSITIONS COMPRISING THE SAME
1. FIELD OF THE INVENTION
Provided herein are quinzolinone derivatives., Pharmaceutical compositions
comprising the compounds are also disclosed.
2. 33A.CKGROUND OF 'MEE INVENTION
2.1 PATHOBIOLOGY OF CANCER Al`W OTHER DISEASES
Cancer is characterized primarily by an increase in the number of abnormal
cells
= derived from a given normal tissue, invasion of adjacent tissues by these
abnormal cells, or
lymphatic or blood-borne spread of malignant .cells to regional lymph nodes
and to distant sites
(metastasis). Clinical data and molecular biologic studies indicate that
cancer is a multistep process
that begins with minor preneoplastic changes, which may under certain
conditions progress to
neoplasia. The neoplastie lesion may evolve clonally and develop an increasing
capacity for
invasion, growth, metastasis, and heterogeneity, especially under conditions
in which the neoplastic
cells escape the host's immune surveillance. Roitt, I., Brostoft 3 and Kale,
D., Immunology, 17.1-
17.12 (3rd ed., Mosby, St. Louis, Mo.,,1993). = .
There is an enormous variety of cancers which are described in detail in the
medical
literature. Examples includes cancer of the lung, colon, rectum, prostate,
breast, brain, and intestine.
The incidence of cancer continues to climb as the general population ages, as
new cancers develop,
and as susceptible populations (e.g., people infected with AIDS or excessively
exposed to sunlight)
grow. However, optiOns for the treatment of cancer are limited. For example,
in the case of blood
cancers (e.g., multiple myeloma), few treatment options are available,
especially when conventional
chemotherapy. fails and bone-marrow transplantation is not an option. A
tremendous demand
therefore exists for new methods and compositions that can be used to treat
patiehts with cancer.
Many types of cancers are associated with new blood vessel formation, a
process
known as angiogenesis. Several of the mechanisms involved in tumor-induced
angiogenesis have
been elucidated. The most direct of these mechanisms is the secretion by the
tumor cells of
cytokines with anglogenic properties. Examples of these cytokines include
acidic and basic
fibroblastic growth factor (sib-FGF), angiogenin, vascular endothelial growth
factor (VEGF), and
TNF-a. Alternatively, tumor cells can release angiogenic peptides through the
production of
proteases and the subsequent breakdown of the extracellular matrix where some
cytokines are stored
(e.g., b-FGF). Angiogenesia can also be induced indirectly through the
recruitment of inflammatory
cells (particularly macrophages) and their subsequent release of angiogenic
cytokines (e.g., TNF-a,
b-FGF).
A Variety of other diseases and disorders are also associated with, or
characterized
by, undesired angiogenesis. For example, enhanced or unregulated angiogenesis
has been
1
=

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WO 2009/042177 PCT/US2008/011124
implicated in a number of diseases and medical conditions including, but not
limited to, ocular
neovascular diseases, choroidal neovascular diseases, retina neovascular
diseases, rubeosis
(neovascularization of the angle), viral diseases, genetic diseases,
inflammatory diseases, allergic
diseases, and autoimmune diseases. Examples of such diseases and conditions
include, but are not
=
limited to: diabetic retinopathy; retinopathy of prematurity; corneal graft
rejection; neovascular
glaucoma; retrolental fibroplasia; arthritis; and proliferative
vitreoretinopathy.
Accordingly, compounds that can control angiogenesis or inhibit the production
of
certain cytokines, including TNFa, may be useful in the treatment and
prevention of various
diseases and conditions.
=
2.2 METHODS OF TREATING CANCER
Current cancer therapy may involve surgery, chemotherapy, hormonal therapy
and/or radiation treatment to eradicate neoplastic cells in a patient (see,
e.g., Stockdale, 1998,
Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV).
Recently, cancer therapy
could also involve biological therapy or immunotherapy. All of these
approaches pose significant
drawbacks for the patient. Surgery, for example, may be contraindicated due to
the health of a
patient or may be unacceptable to the patient. Additionally, surgery may not
completely remove
neoplastic tissue. Radiation therapy is only effective when the neoplastic
tissue exhibits a higher
sensitivity to radiation than normal tissue. Radiation therapy can also often
elicit serious side
effects. Hormonal therapy is rarely given as a single agent. Although hormonal
therapy can be
effective, it is often used to prevent or delay recurrence of cancer after
other treatments have
removed the majority of cancer cells. Biological therapies and immunotherapies
are limited in
number and may produce side effects such as rashes or swellings, flu-like
symptoms, including
fever, chills and fatigue, digestive tract problems or allergic reactions.
With respect to chemotherapy, there are a variety of chemotherapeutic agents
available for treatment of cancer. A majority of cancer chemotherapeutics act
by inhibiting DNA
synthesis, either directly, or indirectly by inhibiting the biosynthesis of
deoxyribonucleotide
triphosphate precursors, to prevent DNA replication and concomitant cell
division. Gilman et al.,
Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Tenth Ed.
(McGraw Hill,
New York).
Despite availability of a variety of chemotherapeutic agents, chemotherapy has

many drawbacks. Stockdale, Medicine, vol. 3, Rubenstein and Federman, eds.,
ch. 12, sect. 10,
1998. Almost all chemotherapeutic agents are toxic, and chemotherapy causes
significant, and often
dangerous side effects including severe nausea, bone marrow depression, and
immunosuppression.
Additionally, even with administration of combinations of chemotherapeutic
agents, many tumor
cells are resistant or develop resistance to the chemotherapeutic agents. In
fact, those cells resistant
to the particular chemotherapeutic agents used in the treatment protocol often
prove to be resistant to
other drugs, even if those agents act by different mechanism from those of the
drugs used in the
specific treatment. This phenomenon is referred to as pleiotropic drug or
multidrug resistance.
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Because of the drug resistance, many cancers prove or become refractory to
standard
chemotherapeutic treatment protocols.
Other diseases or conditions associated with, or characterized by, undesired
angiogenesis are also difficult to treat. However, some compounds such as
protamine, hepain
and steroids have been proposed to be useful in the treatment of certain
specific diseases.
Taylor et al., Nature 297:307 (1982); Folkman et al., Science 221 :719 (1983);
and U.S. Pat.
Nos. 5,001,116 and 4,994,443.
3. SUMMARY OF THE INVENTION
Provided herein are quinazolinone compounds, and pharmaceutically
acceptable salts, solvates (e.g., hydrates), prodrugs, clathrates, or
stereoisomers thereof.
The present disclosure as claimed relates to:
- a compound having a structure of formula (II):
R7
NH
N 1;)
N-=<
R8 (II),
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein: R7 is: halo;
-(CH2)n0H; (Ci-C6)alkyl, optionally substituted with one or more halo; (C1-
C6)alkoxY,
optionally substituted with one or more halo; or (CH2)nNHRd, wherein Rd is:
hydrogen;
(Ci-C6)alkyl, optionally substituted with one or more halo; (CH2)n-(6 to 10
membered aryl);
C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl),
wherein the aryl or heteroaryl is optionally substituted with one or more of:
halo; -SCF3;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or (CI-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(Ci-C8)alkyl, wherein the
alkyl is
optionally substituted with one or more halo; C(0)-(CH2)n-(C3-Cio-cycloalkyl);
C(0)-(CH2)n-
NReRf, wherein Re and Rf are each independently: hydrogen; (Ci-C6)alkyl,
optionally
substituted with one or more halo; (Ci-C6)alkoxy, optionally substituted with
one or more
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halo; or 6 to 10 membered aryl, optionally substituted with one or more of:
halo;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or (Ci-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(CH2)n-04Ci-C6)alkyl; or
C(0)-(CH2)n-0-
(CH2)õ-(6 to 10 membered aryl); R8 is: hydrogen; -(CH2)n0H; phenyl; -0-(Ci-
C6)alkyl; or
(Ci-C6)alkyl, optionally substituted with one or more halo; R9 is: hydrogen;
or (Ci-C6)alkyl,
optionally substituted with one or more halo; and n is 0, 1, or 2;
- a compound having a structure of formula (V):
o o
R15 = NH
0
Ri
R16 (V),
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein: R15 is: halo;
-(CH2)n0H; (Ci-C6)alkyl, optionally substituted with one or more halo; (Ci-
C6)alkoxy,
optionally substituted with one or more halo; or (CH2)nI\IHRi, wherein Ri is:
hydrogen;
(Ci-C6)alkyl, optionally substituted with one or more halo; (CH2)n-(6 to 10
membered aryl);
C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl),
wherein the aryl or heteroaryl is optionally substituted with one or more of:
halo; SCF3;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or (Ci-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(Ci-C8)alkyl, wherein the
alkyl is
optionally substituted with one or more halo; C(0)-(CH2)n-(C3-Cio-cyc1oa1ky1);
C(0)-(CH2)n-
NRkRI, wherein Rk and R' areeach independently: hydrogen; (Ci-C6)alkyl,
optionally
substituted with one or more halo; (C1-C6)alkoxy, optionally substituted with
one or more
halo; or 6 to 10 membered aryl, optionally substituted with one or more of:
halo;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or (Ci-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(CH2)n-0-(C1-C6)a1kyl; or
C(0)-(CH2)n-0-
(CH2)n-(6 to 10 membered aryl); R16 is: hydrogen; -(CH2)n0H; phenyl; -0-(C i-
C6)alkyl; or
(Ci-C6)alkyl, optionally substituted with one or more halo; R17 is: hydrogen;
or (Ci-C6)alkyl,
optionally substituted with one or more halo; and n is 0, 1, or 2;
- a compound having a structure of formula (VI):
3a

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00
1IF
N-2=0
R18 N-__=(
R19R2
(VD,
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein: R18 is: halo;
-(CH2)õOH; (Ci-C6)alkyl, optionally substituted with one or more halo; (Ci-
C6)alkoxy,
optionally substituted with one or more halo; or (CH2)nNEIRm, wherein le is:
hydrogen;
(CI-C6)alkyl, optionally substituted with one or more halo; (CH2)-(6 to 10
membered aryl);
C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl),
wherein the aryl or heteroaryl is optionally substituted with one or more of:
halo; -SCF3;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or (CI-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(Ci-C8)alkyl, wherein the
alkyl is
optionally substituted with one or more halo; C(0)-(CH2)c(C3-C10-cycloalkyl);
C(0)-(CH2)n-
NR"R , wherein le and R are each independently: hydrogen; (Ci-C6)alkyl,
optionally
substituted with one or more halo; (Ci-C6)alkoxy, optionally substituted with
one or more
halo; or 6 to 10 membered aryl, optionally substituted with one or more of:
halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or (Ci-
C6)alkoxy, itself
optionally substituted with one or more halo; C(0)-(CH2)n-0-(Ci-C6)alkyl; or
C(0)-(CH2)n-0-
(CH2)õ-(6 to 10 membered aryl); R19 is hydrogen; -(CH2)n0H; phenyl; -0-(Ci-
C6)alkyl; or
(Ci-C6)alkyl, optionally substituted with one or more halo; R2 is: hydrogen;
or (Ci-C6)alkyl,
optionally substituted with one or more halo; and n is 0, 1, or 2;
- a compound of formula (VII):
R22 R21
00
R23
N0
R24
R25 R2
(VII),
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
wherein: R21 is
hydrogen; R22, R23, and R24 are each independently: halo; -(C1-12)n0H; (Ci-
C6)alkyl,
optionally substituted with one or more halo; (Ci-C6)alkoxy, optionally
substituted with one
3b

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or more halo; or two of R21-R24 together form a 5 to 6 membered ring,
optionally substituted
with one or more of: halo; (C1-C6)alkyl, optionally substituted with one or
more halo; and
(C1-C6)alkoxy, optionally substituted with one or more halo; R25 is: hydrogen;
-(CH2)õOH;
phenyl; -0-(C i-C6)alkyl; or (Ci-C6)alkyl, optionally substituted with one or
more halo; R26 is:
hydrogen; or (Ci-C6)alkyl, optionally substituted with one or more halo; and n
is 0, 1, or 2;
- a compound of formula:
o/
\o 00NH 0 0 Apo C):::r
N_tNH
CI )=0
N-1\1
5
5
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof;
- a pharmaceutical composition comprising a compound as described above, or
a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a
pharmaceutically
acceptable excipient or carrier; and
- use of a compound as described herein, or a pharmaceutically acceptable
salt,
solvate, or stereoisomer thereof, or a pharmaceutical composition as defined
herein, as a
TNFa inhibitor.
4. DETAILED DESCRIPTION OF THE INVENTION
3c

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4.1 COMPOUNDS
In one embodiment, the compounds provided herein have the formula (I):
R2 Rl
0 0
R3 II ts_ni
N 0
R4 14--( R t
R6 (I),
= ,
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
RI is hydrogen;
each of 112, R3, and R4 is independently: hydrogen; halo; -(CHAOH; (Ci-
C6)alkyl, optionally
substituted with one or more halo; (C1-C6)alkoxy, optionally substituted with
one or
more halo; or
-(CH2)nNlile, wherein Ra is:
hydrogen;
= (C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2),-(6 to 10 membered aryl); =
-C(0)-(CH2),,-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with one
or more of: halo; -SCF3; (C1-C6)alkyl, said alkyl itself optionally
substituted with one or more halo; or (C1-C6)alkoxy, said alkoxy itself
optionally substituted with one or more halo;
-C(0)-(C1-C8)allcyl, wherein the alkyl is optionally substituted with one or
more
halo;
-C(0)-(CH2)-(C3-C10-eycloalkyl);
-C(0)-(CH2).-NR111`, wherein RI' and It.' are each independently:
hydrogen;
(Ci-C6)alkyl, optionally substituted with one or more halo;
(Ci-C6)alkoxy, optionally substituted with one or more halo; or
4

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6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)allcyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(0)-(CH2)õ-0-(Ci-C6)alkyl; or
-C(0)-(CH2)n-0-(CH2)-(6 to 10 membered aryl); or
two of R'-R4 together can form a 5 or 6 membered ring, optionally substituted
with one or more of:
halo; (C1-C6)allcyl, optionally substituted with one or more halo; and (C1-
C6)alkoxy,
optionally substituted with one or more halo;
R5 is: hydrogen; -(CH2)n0H; phenyl; -0-(C1-C6)alkyl; or (C1-C6)allcyl,
optionally substituted with
one or more halo;
R6 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In another embodiment, provided herein are compounds of formula (II):
R7
N---=<
R-
R8 (II),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
R7 is: hydrogen; halo; -(CH2).011; (C1-C6)alkyl, optionally substituted with
one or more halo; (C1-
C6)alkoxy, optionally substituted with one or more halo; or
-(CH2)õN1lRd, wherein Rd is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2),-(6 to 10 membered aryl);
-C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with
one or more of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with
one or more halo; or (C1-C6)alkoxy, itself optionally substituted with one
or more halo;
-C(0)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more
halo;
-C(0)-(CH2)-(C3-C10-cycloalkY1);
-C(0)-(CH2)n-NReRf, wherein Re and Rf are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or

CA 02704710 2010-03-23
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6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(0)-(CH2).-0-(C1-C6)alkyl; or
-C(0)-(CH2)-0-(CH2)-(6 to 10 membered aryl);
R8 is: hydrogen; -(CH2)õOH; phenyl; -0-(C1-C6)allcyl; or (Ci-C6)alkyl,
optionally substituted with
one or more halo;
R9 is: hydrogen; or (CI-C6)allcyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In another embodiment, provided herein are compounds of formula (III):
R1.
Aik 0 0
N--K Ri2 _____________________________
R11 (III),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
R19 is: hydrogen; halo; -(CH2).0H; (C1-C6)alkyl, optionally substituted with
one or more halo; or
(C1-C6)alkoxy, optionally substituted with one or more halo;
R11 is: hydrogen; -(CH2)OH; phenyl; -0-(Ci-C6)alkyl; or (Ci-C6)allcyl,
optionally substituted with
one or more halo;
R12 is: hydrogen; or (C1-C6)allcyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In one embodiment, le is hydrogen. In another embodiment, RI is halo. In
another embodiment, R19 is (C1-C6)allcyl, optionally substituted with one or
more halo. In another
embodiment, R19 is -(CH2)OH or hydroxyl. In another embodiment, R19 is (C1-
C6)alkoxy,
optionally substituted with one or more halo.
In one embodiment, R" is hydrogen. In another emdodiment, R" is -(CH2)õOH or
hydroxyl. In another emdodiment, R" is phenyl. In another emdodiment, R" is -0-
(C1-C6)alkyl,
optionally substituted with one or more halo. In another emdodiment, R" is (C1-
C6)allcyl, optionally
substituted with one or more halo.
In one embodiment, R12 is hydrogen. In another embodiment, R12 is (C1-
C6)allcyl,
optionally substituted with one or more halo.
In one embodiment, n is 0. In another embodiment, n is 1. In another
embodiment,
n is 2.
Compounds provided herein encompass any of the combinations of R1 , R12
and n described above.
In one specific embodiment, R19 is halo. In another embodiment, le is
hydroxyl.
In another embodiment, RI is methyl.
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In another specific embodiment, R11 is hydrogen. In another embodiment, R" is
methyl.
In another specific embodiment, R.12 is hydrogen. In another embodiment, R12
is
methyl.
Specific compounds include, but are not limited to:
CI
0 N 0
0 0 0
N-tN0
N
N=
Br
0 0
N N-t
HO 0 0 CI 0 0
N 0 N
Br
00H0 0
N-tN= N-=/
,or
In another embodiment, provided herein are compounds of formula (IV):
( F12)n-NHR8
0 0
R14 _________________________________
R13 (W),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
Rg is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)11-(6 to 10 membered aryl);
-C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with
one or more of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with
one or more halo; or (Ci-C6)alkoxy, itself optionally substituted with one
or more halo;
-C(0)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more
halo;
-C(0)-(CH2)-(C3-C10-cycloallcyl);
-C(0)-(CH2)-NRhRi, wherein Rh and RI are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
7

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6 to 10 membered aryl, optionally substituted with one or more of: halo;
(Ci-C6)allcyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(0)-(CH2)n-0-(CI-C6)alkyl; or
-C(0)-(CH2)õ-0-(CH2)õ-(6 to 10 membered aryl);
R13 is: hydrogen; -(CH2)110H; phenyl; -0-(CI-C6)alkyl; or (Ci-C6)alkyl,
optionally substituted with
one or more halo;
R14 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In one embodiment, Rg is hydrogen. In abother embodiment, Rg is (C1-C6)alkyl,
optionally substituted with one or more halo. In abother embodiment, Rg is -
(CH2)n-(6 to 10
membered aryl). In abother embodiment, Rg is -C(0)-(CH2).-(6 to 10 membered
aryl) or -C(0)-
(CH2)n-(6 to 10 membered heteroaryl), wherein the aryl or heteroaryl is
optionally substituted as
described above. In abother embodiment, Rg is -C(0)-(Ci-C8)alkyl, wherein the
alkyl is optionally
substituted with one or more halo. In abother embodiment, Rg is -C(0)-(CH2)-
(C3-C10-cycloalkyl).
In abother embodiment, Rg is -C(0)-(CH2)n-NRhRi, wherein Rh and Ri are as
described above. In
abother embodiment, Rg is -C(0)-(CH2)-0-(C1-C6)alkyl. In abother embodiment,
Rg is -C(0)-
(CH2)n-0-(CH2)õ-(6 to 10 membered aryl).
In one embodiment, R13 is hydrogen. In another emdodiment, R13 is -(CH2)n0H or

hydroxyl. In another emdodiment, R13 is phenyl. In another emdodiment, R13 is -
0-(C1-C6)alkyl,
optionally substituted with one or more halo. In another emdodiment, R13 is
(Ci-C6)allcyl, optionally
substituted with one or more halo.
In one embodiment, R14 is hydrogen. In another embodiment, R14 is (Ci-
C6)allcyl,
optionally substituted with one or more halo.
In one embodiment, n is 0. In another embodiment, n is 1. In another
embodiment,
n is 2.
Compounds provided herein encompass any of the combinations of Rg, R13, R14
and
n described above.
In one specific embodiment, Rg is hydrogen, and n is 0 or 1. In another
embodiment, Rg is -C(0)-(C1-C6)alkyl. In another embodiment, Rg is -C(0)-
phenyl, optionally
substituted with one or more methyl, halo, and/or (C1-C6)alkoxy.
In another specific embodiment, R13 is methyl. In another embodiment, R14 is
hydrogen.
Specific compounds include, but are not limited to:
NH
0 0 0 *
0 ill 00
H2N 0 0 0
*
0
t1=-
5
5
8

CA 02704710 2010-03-23
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H-Cl 0 NH NH
H2N
0 0
4, µ(:) W N -- 0_0t. 0 E>.--0
w
A-m- O_Otri
N-tN
0 N 0
N=c ______________________________ N=c N.=
3 3
0 0
\ NH HN-4
* HN 0 HN
t1s1
/ 0 W
N 0
* N-tNj *
=c CI
N 0 0
3 N-= N=c
3 3
0 9 0
HN-4 HN-4' HN4
0 HN 4c: HN 0 HN
*0 0
0
/ N- 0 0
Si ....1 0 0
11/ _ N___N0
Cl ' N 0 0
N=c N= F-4-F N---
F
3 3 3
0
=HN HN-4 . HN
FS p 0 0
F( 0 0 0 HN CI * > CI 0 0 la
Ni_tiN)=Jo
F N 0
I/1= lit N-b=0 0 N=c
3
* 0
ii HN CI
HN
F HN
F 0 0, F- NX 0 . _t_INI 0 CI 41 0 CL
F it N-Cpj F 0 *
/ 0
0 N".= 1=1=
1=1== 5 , or
, .
F F ak 0
F W HN
00
*
N-\_FO
iµl=.
In another embodiment, provided herein are compounds of formula (V):
.--- 0 0
R15 W _?,N___i
N 0
N=X R1
R16
(V),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
R15 is: hydrogen; halo; -(CH2)OH; (C1-C6)alkyl, optionally substituted with
one or more halo; (C1-
C6)alkoxy, optionally substituted with one or more halo; or
-(CHOnNHRi, wherein Ri is:
hydrogen;
(C1-C6)allcyl, optionally substituted with one or more halo;
-(CH2),;(6 to 10 membered aryl);
-C(0)-(CH2)õ-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with
one or more of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with
9

CA 02704710 2010-03-23
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one or more halo; or (C1-C6)alkoxy, itself optionally substituted with one
or more halo;
-C(0)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more
halo;
-C(0)-(CH2)n-(C3-C10-cycloalkyl);
-C(0)-(CH2)n-NRkR1, wherein Rk and R1 are each independently:
hydrogen;
(Ci-C6)allcyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
6 to 10 membered aryl, optionally substituted with one or more of: halo;
(C1-C6)alkyl, itself optionally substituted with one or more halo; or
(C1-C6)alkoxy, itself optionally substituted with one or more halo;
-C(0)-(CH2)n-0-(C1-C6)alkyl; or
-C(0)-(CH2)n-0-(CH2)n-(6 to 10 membered aryl);
R16 is: hydrogen; -(CH2)n0H; phenyl; -0-(C1-C6)alkyl; or (C1-C6)allcyl,
optionally substituted with
one or more halo;
R17 is: hydrogen; or (C1-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In one embodiment, R15 is hydrogen. In another embodiment, R15 is halo. In
another embodiment, R15 is (C1-C6)allcyl, optionally substituted with one or
more halo. In another
embodiment, R15 is -(CH2)n0H or hydroxyl. In another embodiment, R15 is (C1-
C6)alkoxy,
optionally substituted with one or more halo.
In one embodiment, R15 is -(CH2),NITIV. In one embodiment, wherein R15 is -
(CH2)nNHIV, IV is hydrogen. In another embodiment, R1 is (C1-C6)alkyl,
optionally substituted with
one or more halo. In another embodiment, Ri is -(042)no to 10 membered aryl).
In another
embodiment, Ri is -C(0)-(CH2)õ-(6 to 10 membered aryl) or -C(0)-(CH2)õ-(6 to
10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted as
described above. In another
embodiment, k is -C(0)-(C1-C8)alkyl, wherein the alkyl is optionally
substituted with one or more
halo. In another embodiment, Ri is -C(0)-(CH2)n-(C3-Cio-cycloallcyl). In
another embodiment, R is
-C(0)-(CH2)õ-NRkR1, wherein Rk and RI are as described above. In another
embodiment, Ri is -
C(0)-(CH2)õ-0-(C1-C6)a1kyl. In another embodiment, Ri is -C(0)-(CH2)-0-(CH2)n-
(6 to 10
membered aryl).
In one embodiment, R16 is hydrogen. In another embodiment, R16 is -(CH2)n0H or

hydroxyl. In another embodiment, R16 is phenyl. In another embodiment, R16 is -
0-(C1-C6)alkyl,
optionally substituted with one or more halo. In another embodiment, R16 is
(C1-C6)alkyl, optionally
substituted with one or more halo.
In one embodiment, R17 is hydrogen. In another embodiment, R17 is (C1-
C6)alkyl,
optionally substituted with one or more halo.

CA 02704710 2010-03-23
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In one embodiment, n is 0. In another embodiment, n is 1. In another
embodiment,
n is 2.
Compounds provided herein encompass any of the combinations of R15, R16, R17
and n described above.
In one specific embodiment, R15 is methyl. In another embodiment, R15 is halo.
In
another embodiment, R15 is -CF3. In another embodiment, R15 is -(CH2)õNHRJ.
In one specific embodiment wherein R15 is -(CHAINHW, W is hydrogen, and n is 0

or 1. In another embodiment wherein R15 is -(CH2)NRW, W is -C(0)-(0)-(C1-
C6)alkyl.
In one specific embodiment, R16 is hydrogen. In another embodiment, R16 is
methyl. In another specific embodiment, R17 is hydrogen or methyl.
Specific compounds include, but are not limited to:
0,N 0 Cl
0 0
0 =
N
N=c ____________________________________
3
5
0 N 00 n1 0
0 0 yj0 0
N
F F F N=/
Br
0
0 )L0 *
N 11=c
N 0
N--=/
5 H2N
IJ
5
H-Cl
0 0
or =
H2N N 0
In another embodiment, provided herein are compounds of formula (VI):
0 0
_Z¨NH
R18 N=(
R19 (VI),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
R18 is: hydrogen; halo; -(CH2)OH; (C1-C6)alkyl, optionally substituted with
one or more halo; (C1-
C6)alkoxy, optionally substituted with one or more halo; or
-(CH2)õNHilr, wherein Rm is:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
-(CH2)õ-(6 to 10 membered aryl);
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-C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)n-(6 to 10 membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted with
one or more of: halo; -SCF3; (C1-C6)alkyl, itself optionally substituted with
one or more halo; or (C1-C6)alkoxy, itself optionally substituted with one
or more halo;
-C(0)-(C1-C8)alkyl, wherein the alkyl is optionally substituted with one or
more
halo;
-C(0)-(CH2)-(C3-C10-cycloalkyl);
-C(0)-(CH2)n-NR11. , wherein R and R are each independently:
hydrogen;
(C1-C6)alkyl, optionally substituted with one or more halo;
(C1-C6)alkoxy, optionally substituted with one or more halo; or
6 to 10 membered aryl, optionally substituted with one or more of: halo;
(Ci-C6)alkyl, itself optionally substituted with one or more halo; or
(Ci-C6)alkoxy, itself optionally substituted with one or more halo;
-C(0)-(CH2).-0-(C1-C6)alkyl; or
-C(0)-(CH2).-0-(CH2)-(6 to 10 membered aryl);
R19 is: hydrogen; -(CH2)n0H; phenyl; -0-(C1-C6)alkyl; or (Ci-C6)alkyl,
optionally substituted with
one or more halo;
R2 is: hydrogen; or (Ci-C6)alkyl, optionally substituted with one or more
halo; and
n is 0, 1, or 2.
In one embodiment, R18 is hydrogen. In another embodiment, R18 is halo. In
another embodiment, R18 is (Ci-C6)alkyl, optionally substituted with one or
more halo. In another
embodiment, le8 is -(CH2)n0H or hydroxyl. In another embodiment, R18 is (C1-
C6)alkoxY,
optionally substituted with one or more halo.
In one embodiment, R18 is -(CH2)nNlilr. In one embodiment, wherein R28 is -
(CH2)NIIRs, Rs is hydrogen. In another embodiment, RI is (C1-C6)alkyl,
optionally substituted
with one or more halo. In another embodiment, WI is -(CH2)n-(6 to 10 membered
aryl). In another
embodiment, le is -C(0)-(CH2)n-(6 to 10 membered aryl) or -C(0)-(CH2)-(6 to 10
membered
heteroaryl), wherein the aryl or heteroaryl is optionally substituted as
described above. In another
embodiment, Rs is -C(0)-(C1-C8)alkyl, wherein the alkyl is optionally
substituted with one or more
halo. In another embodiment, RI' is -C(0)-(CH2)-(C3-C10-cycloalkyl). In
another embodiment, Ir
is -C(0)-(CH2)n-NIVR , wherein R and R are as described above. In another
embodiment, Rm is -
C(0)-(CH2)n-0-(CI-C6)alkyl. In another embodiment, lel is -C(0)-(CH2)n-00-
(CH2)-(6 to 10
membered aryl).
In one embodiment, R19 is hydrogen. In another embodiment, R19 is -(CH2)n0H or

hydroxyl. In another embodiment, R'9 is phenyl. In another embodiment, R19 is -
0-(C1-C6)alkyl,
optionally substituted with one or more halo. In another embodiment, R19 is
(Ci-C6)alkyl, optionally
substituted with one or more halo.
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In one embodiment, R2 is hydrogen. In another embodiment, R2 is (CI-
C6)allcyl,
optionally substituted with one or more halo.
In one embodiment, n is 0. In another embodiment, n is 1. In another
embodiment,
n is 2.
Compounds provided herein encompass any of the combinations of R18, R19, R20
and n described above.
In one specific embodiment, R18 is methyl. In another embodiment, R18 is halo.
In
another embodiment, R18 is hydroxyl. In another embodiment, R18 is -CF3.
In one specific embodiment, R19 is hydrogen. In another embodiment, R19 is
methyl. In another specific embodiment, R2 is hydrogen.
Specific compounds include, but are not limited to:
0
0 N 0 0 N, ,0 0 N 0
0 0
N N
410
(%(-j
CI
0,N 0
0
0 N 0 0ii 0
*,*".. s".";;;"
010
Br OH F F
,or
=
N=j __________
In another embodiment, provided herein are compounds of formula (VII):
R22 R21
Aik 0 0
R23 w NH
0
Rza N=¨X
R2
R25 (VII),
and pharmaceutically acceptable salts, solvates, and stereoisomers thereof,
wherein:
R21 is hydrogen;
R22, I( ¨23,
and R24 are each independently: halo; -(CH2)n0H; (C1-C6)alkyl, optionally
substituted with
one or more halo; (C1-C6)alkoxy, optionally substituted with one or more halo;
or
two of R21-R24 together form a 5 to 6 membered ring, optionally substituted
with one or more of:
halo; (C1-C6)alkyl, optionally substituted with one or more halo; and (C1-
C6)alkoxy,
optionally substituted with one or more halo;
R25 is: hydrogen; -(CH2)OH; phenyl; -0-(C1-C6)alkyl; or (C1-C6)allcyl,
optionally substituted with
one or more halo;
R26 is: hydrogen; or (C1-C6)allcyl, optionally substituted with one or more
halo; and
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n is 0, 1, or 2.
In one embodiment, two of R22-R24 are halo. In another embodiment, two of R22-
R24 are (C1-C6)alkyl, optionally substituted with one or more halo. In another
embodiment, two of
K R24 are (Ci-C6)alkoxy, optionally substituted with one or more halo.
In another embodiment, one of R22-R24 are is halo, and another one of R22-R24
is
(Ci-C6)allcyl, optionally substituted with one or more halo. In another
embodiment, one of R22-R24
is halo, and another one of R22-R24 is (Ci-C6)alkoxy, optionally substituted
with one or more halo.
In another embodiment, one of R22-R24 is (C1-C6)alkoxy, optionally substituted
with one or more
halo, and another one of R22-R24 is (C1-C6)alkyl, optionally substituted with
one or more halo.
In another embodiment, two of R22-R24 together form a 5 to 6 membered ring. In

one specific embodiment, R22 and R23 together form a 5 to 6 membered ring. In
one specific
embodiment, R22 and R23 together form phenyl ring. In another embodiment, the
ring formed by R22
and R23 is optionally substituted with one or more of: halo; (C1-C6)alkyl,
optionally substituted with
one or more halo; and (C1-C6)alkoxy, optionally substituted with one or more
halo.
In one embodiment, R25 is hydrogen. In another embodiment, R25 is -(CH2)OH or
hydroxyl. In another embodiment, R25 is phenyl. In another embodiment, R25 is -
0-(C1-C6)alkyl,
optionally substituted with one or more halo. In another embodiment, R25 is
(C1-C6)alkyl, optionally
substituted with one or more halo.
In one embodiment, R26 is hydrogen. In another embodiment, R26 is (C1-
C6)allcyl,
optionally substituted with one or more halo.
In one embodiment, n is 0. In another embodiment, n is 1. In another
embodiment,
n is 2.
Compounds provided herein encompass any of the combinations of R21, R22, R23,
R24, R25,
and n described above.
Specific compounds include, but are not limited to:
0 e
01 0
0 0 lk
N
N N=c
CI
,or
As used herein, and unless otherwise specified, the term "pharmaceutically
acceptable salt" refers to salts prepared from pharmaceutically acceptable non-
toxic acids, including
inorganic acids and organic acids. Suitable non-toxic acids include inorganic
and organic acids such
as, but not limited to, acetic, alginic, anthranilic, benzenesulfonic,
benzoic, camphorsulfonic, citric,
ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,
galacturonic, glycidic,
hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic,
nitric, pamoic, pantothenic, phenylacetic, propionic, phosphoric, salicylic,
stearic, succinic,
sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. In one
embodiment, suitable are
hydrochloric, hydrobromic, phosphoric, and sulfuric acids.
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As used herein, and unless otherwise specified, the term "solvate" means a
compound that further includes a stoichiometric or non-stoichiometric amount
of solvent bound by
non-covalent intermolecular forces. Where the solvent is water, the solvate is
a hydrate.
As used herein, and unless otherwise specified, the term "prodrug" means a
derivative of a compound that can hydrolyze, oxidize, or otherwise react under
biological conditions
(in vitro or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to,
compounds that comprise biohydrolyzable moieties such as biohydrolyzable
amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable
ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs
include compounds
that comprise -NO, -NO2, -ONO, or -0NO2 moieties. Prodrugs can typically be
prepared using
well-known methods, such as those described in Burger's Medicinal Chemistry
and Drug
Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design
of Prodrugs (H.
Bundgaard ed., Elselvier, New York 1985).
As used herein, and unless otherwise specified, the terms "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide" and
"biohydrolyzable
phosphate "mean a carbamate, carbonate, ureide and phosphate, respectively, of
a compound that
either: 1) does not interfere with the biological activity of the compound but
can confer upon that
compound advantageous properties in vivo, such as uptake, duration of action,
or onset of action; or
2) is biologically inactive but is converted in vivo to the biologically
active compound. Examples of
biohydrolyzable carbamates include, but are not limited to, carbamates that
include lower
alkylamine, substituted ethylenediamine, aminoacid, hydroxyalkylamine,
heterocyclic and
heteroaromatic amine, and polyether amine moieties.
As used herein, and unless otherwise specified, the term "stereoisomer"
encompasses all enantiomerically/stereomerically pure and
enantiomerically/stereomerically
enriched compounds provided herein.
As used herein and unless otherwise indicated, the term "stereomerically pure"

means a composition that comprises one stereoisomer of a compound and is
substantially free of
other stereoisomers of that compound. For example, a stereomerically pure
composition of a
compound having one chiral center will be substantially free of the opposite
enantiomer of the
compound. A stereomerically pure composition of a compound having two chiral
centers will be
substantially free of other diastereomers of the compound. A typical
stereomerically pure
compound comprises greater than about 80% by weight of one stereoisomer of the
compound and
less than about 20% by weight of other stereoisomers of the compound, greater
than about 90% by
weight of one stereoisomer of the compound and less than about 10% by weight
of the other
stereoisomers of the compound, greater than about 95% by weight of one
stereoisomer of the
compound and less than about 5% by weight of the other stereoisomers of the
compound, or greater
than about 97% by weight of one stereoisomer of the compound and less than
about 3% by weight
of the other stereoisomers of the compound.

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As used herein and unless otherwise indicated, the term "stereomerically
enriched"
means a composition that comprises greater than about 554.4 by weight of one
stereoisomer of a
compound, greater than about 60% by weight of one stereoisomer of a compound,
greater than about
70% by weight, or greater than about 80% by weight of one stereoisomer of a
compound.
As used herein, and unless otherwise indicated, the term "enantiomerically
pure"
means a stereomerically pure composition of a compound having one chiral
center. Similarly, the
term "enantiomerically enriched" means a stereomerically enriched composition
of a compound
having one chiral center.
As used herein, and unless otherwise indicated, the term "alkyl" refers to a
saturated
straight chain or branched hydrocarbon having a number of carbon atoms as
specified herein.
Representative saturated straight chain alkyls include -methyl, -ethyl,,
-n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyls
include
-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-
methylbutyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl,
4-methythexyl, 5-methylhexyl, 2,3-dimethylbutyl, and the like. The term
"alkyl" also encompasses
cycloalkyl.
As used herein, and unless otherwise specified, the term "cycloalkyl" means a
specie of alkyl containing from 3 to 15 carbon atoms, without alternating or
resonating double bonds
between carbon atoms. It may contain from Ito 4 rings. Examples of
unsubstituted cycloallcyls
include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and adamantyl. A
cycloalkyl may be substituted with one or more of the substituents.
As used herein, the term "aryl" means a carbocyclic aromatic ring containing
from 5
to 14 ring atoms. The ring atoms of a carbocyclic aryl group are all carbon
atoms. Aryl ring
structures include compounds having one or more ring structures such as mono-,
bi-, or tricyclic
compounds as well as benzo-fused carbocyclic moieties such as 5,6,7,8-
tetrahydronaphthyl and the
like. Specifically, the aryl group is a monocyclic ring or bicyclic ring.
Representative aryl groups
include phenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl and
naphthyl.
It should be noted that if there is a discrepancy between a depicted structure
and a
name given that structure, the depicted structure is to be accorded more
weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not indicated
with, for example, bold or
dashed lines, the structure or portion of the structure is to be interpreted
as encompassing all
stereoisomers of it.
4.2 METHODS OF TREATMENT. PREVENTION AND MANAGEMENT
A compound provided herein, or a pharmaceutically acceptable salt, solvate
(e.,
hydrate), prodrug, clathrate, or stereoisomer thereof, may potentially be
useful in methods of treating,
preventing and/or managing various diseases or disorders. Without being
limited by a particular theory,
compounds provided herein may potentially control angiogenesis or inhibit the
production of
certain cytokines including, but not limited to, TNF-a, IL-10, IL-12, IL-18,
GM-CSF, and/or IL-6.
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Without being limited by a particular theory, compounds provided herein may
potentially stimulate the production of
certain other cytokines including IL- 10, and also act as a costimulatory
signal for T cell activation, resulting in
increased production of cytokines such as, but not limited to, IL- 12 and/or
IFN-y. In addition, compounds provided
herein may potentially,enhance the effects of NK cells and antibody-mediated
cellular cytotoxicity (ADCC). Further,
compounds provided herein may be immunomodulatory and/or cytotoxic, and thus,
may potentially be useful as
chemotherapeutic agents. In some embodiments, compounds provided herein were
found to
inhibit TNFa, and/or stimulate the
production of IL-2, and/or inhibit proliferation of Namalwa A04 cells.
Consequently, without being limited by a
particular theory, some or all of such characteristics possessed by the
compounds provided herein may render them
potentially useful in treating, managing, and/or preventing various diseases
or disorders.
Examples of diseases or disorders may include, but are not limited to, cancer,
disorders associated
with angiogenesis, pain including, but not limited to, Complex Regional Pain
Syndrome ("CAPS"), Macular
Degeneration ("MD") and related syndromes, skin diseases, pulmonary disorders,
asbestos-related disorders, parasitic
diseases, immunodeficiency disorders, CNS disorders, CNS injury,
atherosclerosis and related disorders, dysfunctional
sleep and related disorders, hemoglobinopathy and related disorders (e.g.,
anemia), TNFa related disorders, and other
various diseases and disorders.
As used herein, and unless otherwise specified, the terms "treat," "treating"
and
"treatment" refer to the eradication or amelioration of a disease or disorder,
or of one or more
symptoms associated with the disease or disorder. In certain embodiments, the
terms refer to
minimizing the spread or worsening of the disease or disorder resulting from
the administration of
one or more prophylactic or therapeutic agents to a subject with such a
disease or disorder. In some
embodiments, the terms refer to the administration of a compound provided
herein, with or without
other additional active agent, after the onset of symptoms of the particular
disease. =
= As used herein, and unless otherwise specified, the terms "prevent,"
"preventing"
and "prevention" refer to the prevention of the onset, recurrence or spread of
a disease or disorder,
or of one or more symptoms thereof. In certain embodiments, the terms refer to
the treatment with
or administration of a compound provided herein, with or without other
additional active compound,
prior to the onset of symptoms, particularly to patients at risk of disease or
disorders provided
herein. The terms encompass the inhibition or reduction of a symptom of the
particular disease.
Patients with familial history of a disease in particular are candidates for
preventive regimens in
certain embodiments. In addition, patients who have a history of reccurring
symptoms are also
potential candidates for the prevention. In this regard, the term "prevention"
may be
interchangeably used with the term "prophylactic treatment."
As used herein, and unless otherwise specified, the terms "manage," "managing"

and "management" refer to preventing or slowing the progression, spread or
worsening of a disease
or disorder, or of one or more symptoms thereof. Often, the beneficial effects
that a subject derives
from a prophylactic and/or therapeutic agent do not result in a cure of the
disease or disorder. In this
regard, the term "managing" encompasses treating a patient who had suffered
from the particular
disease in an attempt to prevent or minimize the recurrence of the disease.
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As used herein, and unless otherwise specified, a "therapeutically effective
amount"
of a compound is an amount sufficient to provide a therapeutic benefit in the
treatment or
management of a disease or disorder, or to delay or minimize one or more
symptoms associated with
the disease or disorder. A therapeutically effective amount of a compound
means an amount of
therapeutic agent, alone or in combination with other therapies; which
provides a therapeutic benefit
in the treatment or management of the disease or disorder. The term
"therapeutically effective
amount" can encompass an amount that improves overall therapy, reduces or
avoids symptoms or
causes of disease or disorder, or enhances the therapeutic efficacy of another
therapeutic agent.
As used herein, and unless otherwise specified, a "prophylactically effective
amount" of a compound is an amount sufficient to prevent a disease or
disorder, or prevent its
recurrence. A prophylactically effective amount of a compound means an amount
of therapeutic
agent, alone or in combination with other agents, which provides a
prophylactic benefit in the
prevention of the disease. The term "prophylacticallyeffective amount" can
encompass an amount
that improves overall prophylaxis or enhances the prophylactic efficacy of
another prophylactic
agent.
Examples of cancer and precancerous conditions may include, but are not
limited to,
those described in U,S. patent nos. 6,281,230 and 5,635,517 to Muller et al.,
in various U.S. patent
publications to Zeldis, including publication nos. 2004/0220144A1, published
November 4, 2004
(Treatment of Myelodysplastic Syndrome); 2004/0029832A1, published February
12,2004
(Treatment of Various Types of Cancer); and 2004/0087546, published May 6,
2004 (Treatment of
Myeloproliferative.Diseases). Examples may also include those described in WO
2004/103274,
published December 2, 2004.
Specific examples of cancer may include, but are not limited to, cancers of
the skin, such
as melanoma; lymph node; breast; cervix; Menu; gastrointestinal tract; lung;
ovary; prostate; colon;
rectum; mouth; brain; head and neck; throat; testes; kidney; pancreas; bone;
spleen liver; bladder,
larynx; nasal passages; and AIDS-related cancers. The compounds may also be
potentially useful for
treating cancers of the blood and bone marrow, such as multiple myeloma and
acute and chronic
leukemias, for example, lymphoblastic, myelogenous, lymphocytic, and
myelocytic leukemias. The
compounds provided herein may potentially be used for treating, preventing or
managing either primary
or metastatic tumors.
Other specific cancers may include, but are not limited to, advanced
malignancy,
amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain
metastase,
glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor,
malignant glioma, recurrent malignant glioma, anaplastic astrocytoma,
anaplastic
oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D
colorectal cancer,
unresectable colorectal carcinoma, metastatic hepatocellular carcinoma,
Kaposi's sarcoma, karotype
acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's
lymphoma, non-
Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma,
diffuse large B-
18

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Cell lymphoma, low grade follicular lymphoma, metastatic melanoma (localized
melanoma, =
including, but not limited to, ocular melanoma), malignant mesothelioma,
malignant pleural effusion
mesothelioma syndrome; peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma,
soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell
histiocytosis,
=
Ieiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory
prostate cancer, resected
high-risk soft tissue sarcoma, unrescectable hepatocellular carcinoma,
Waldensh-om's
= macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube
cancer, androgen
independent prostate cancer, androgen dependent stage IV non-metastatic
prostate cancer, hormone-
insensitive prostate cancer, chemotherapy-insensitive prostate cancer,
papillary thyroid carcinoma,
follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. jn a
specific
embodiment, the cancer maybe mestatic. In another embodiment, the cancer may
be refractory or resistance
to chemotherapy or radiation. =
In one embodiment, provided herein are methods that may potentially treat,
prevent or -
manage various forms of leukemias such as chronic lymphoctic leukemia, chronic
myelocytic
leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia and acute
myeloblastic
leukemia, including leukemias that are relapsed, refractory or resistant, as
disclosed in U.S.
publication no. 2006/0030594, published February 9, 2006.
The term "leukemia" refers malignant neoplasms of the blood-forming tissues.
The
leukemia may include, but is not limited to, chronic lymphocytic leukemia,
chronic myelocytic
leukemia, acute lymphoblastic leukemia, acute myplogenous leukemia and acute
myeloblastic
leukemia. The leukemia may be relapsed, refractory or resistant to
conventional therapy. The term
"relapsed" refers to a situation where patients who have had a remission of
leukemia after therapy
have a return of leukemia cells in the marrow and a decrease in normal blood
cells. The .term
"refractory or resistant" refers to a circumstance where patients, even after
intensive treatment, have
residual leukemia cells in their marrow.
In another embodiment, provided herein are methods that may potentially treat,
prevent or
manage various types of lymphomas, including Non-Hodgkin's lymphoma (NHL). The
term
"lymphoma" refers a heterogenous group of neoplasms arising in the
reticuloendothelial and
lymphatic systems. "NHL" refers to malignant monoclonal proliferation of
lymphoid cells in sites
of the immune system, including lymph nodes, bone marrow, spleen, liver and
gastrointestinal tract.
Examples of NHL. may include, but are not limited to, mantle cell lymphoma
(MCL), lymphocytic
lymphoma of intermediate differentiation, intermediate lymphocytic lymphoma
(ILL), diffuse
poorly differentiated lymphocytic lymphoma (PDL), centrocytic lymphoma,
diffuse small-cleaved =
cell lymphoma (DSCCL), follicular lymphoma, and any type of the mantle cell
lymphomas that can
be seen under the microscope (nodular, diffuse, blastic and mentle zone
lymphoma).
Examples ofdiseases and disorders associated with, or characterized by,
undesired
angiogenesis may include, but are not limited to, inflammatory diseases,
autoimmune diseases, viral
diseases, genetic diseases, allergic diseases, bacterial diseases, ocular
neovascular diseases,
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choroidal neovascular diseases, retina neovascular diseases, and rubeosis
(neovascularization of the
angle). Specific examples of the diseases and disorders associated with, or
characterized by,
undesired angiogenesis may include, but are not limited to, arthritis,
endometriosis, Crohn's disease,
heart failure, advanced heart failure, renal impairment, endotoxemia, toxic
shock syndrome,
osteoarthritis, retrovirus replication, wasting, meningitis, silica-induced
fibrosis, asbestos-induced
fibrosis, veterinary disorder, malignancy-associated hypercalcemia, stroke,
circulatory shock,
periodontitis, gingivitis, macrocytic anemia, refractory anemia, and 5q-
deletion syndrome.
Examples of pain may include, but are not limited to those described in U.S.
patent
publication no. 2005/0203142, published September 15, 2005.
Specific types of pain may include, but are not limited to, nociceptive pain,
neuropathic pain,
mixed pain of nociceptive and neuropathic pain, visceral pain, migraine,
headache and post-
operative pain.
Examples of nociceptive pain may include, but are not limited to, pain
associated with
chemical or thermal bums, cuts of the skin, cbntusions of the skin,
osteoarthritis, rheumatoid
arthritis, tendonitis, and mydfascial pain.
Examples of neuropathic pain may include but are not limited to, CRPS type I,
CRPS
type II, reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy,
reflex dystrophy,
sympathetically maintained pain syndrome, causalgia, Sudeck atrophy of bone,
algoneurodystrophy,
shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia, post
herpetic neuralgia, ,
cancer related pain, phantom limb pain, fibromyalgia, chronic fatigue
syndrome, spinal cord injury
pain, central post-stroke pain, radiculopathy, diabetic neuropathy, post-
stroke pain, luetic
neuropathy, and other painful neuropathic conditions such as those induced by
drugs such as
vincristine and velcade.
As used herein, the terms "complex regional pain syndrome," "CRPS" and "CRPS
and related syndromes" mean a chronic pain disorder characterized by one or
more of the following:
pain, whether spontaneous or evoked, including allodynia (painful response to
a stimulus that is not
usually painful) and hypemlgesla (exaggerated response to a stimulus that is
usually only mildly
painful); pain that is disproportionate to the inciting event (e.g., years of
severe pain after an ankle
sprain); regional pain that is not limited to a single peripheral nerve
distribution; and autonomic
dysregulation (e.g., edema, alteration in blood flow and hyperhidrosis)
associated with trophic skin
changes (hair and nail growth abnormalities and cutaneous ulceration).
Examples of MD and related syndromes may include, but are not limited to,
those
described in U.S. patent publication no. 2004/0091455, published May 13. 2004,
Specific examples may include, but are not limited to, atrophic (dry)
MD, exudative (wet) MD, age-related maculopathy (ARM), choroidal
neovascularisation (CNVM),
retinal pigment epithelium detachment (PED), and atrophy of retinal pigment
epithelium (RPE).
Examples of skin diseases may include, but are not limited to, those described
in U.S.
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Specific examples may include, but are not limited to, keratosis and related
symptoms, skin
diseases or disorders characterized with overgrowths of the epidermis, Acne,
and wrinkles.
As used herein, the term "keratosib" refers to any lesion on the epidermis
marked by
the presence of circumscribed overgrowths of the horny layer, including but
not limited to actinic
keratosis, seborrheic keratosis, kemtoacanthoma, keratosis follicularis
(Darier disease), inverted
follicular keratosis, palmop. tenter ketatoderma (PPK, keratosis palmaris et
plantaris), keratosis
pilaris, and stucco keratosis. The term "actinic keratosis" also refers to
senile keratosis, keratosis
senilis, verruca seals, plane senilis, solar keratosis, keratoderma or
keratoma. The term "seborrheic
keratosis" also refers to seborrheic wart, senile wart, or basal cell
papilloma. Keratosis is
characterized by one or more of the, following iymptoms:. rough appearing,
scaly, elythematous
papules, plaques, spicules or nodules on exposed surfaces (e.g., face, hands,
ears, neck, legs and
thorax), excrescentes of keratin referred to as cutaneous horns,
hyperkeratosis, telangiectasias,
elastosis, pigmented lentigines, acanthosis, parakeratosis, dyskemtoses,
papillomatosis,
hyperpigmentation of the basal cells, cellular atypia, mitotic figures,
abnormal cell-cell adhesion,
denseinflammatory infiltrates and small prevalence of squamous cell
carcinomas.
Examples of skin diseases or disorders characterized with overgrowths of the
epidermis may include, but are not limited to, any conditions, diseases or
disorders marked by the
presence of overgrowths of the epidermis, including but not limited to,
infections associated with
papilloma virus, arsenical keratoses, sign of Leser-Trelat, warty dyskeratoma
(WD), trichostasis
spinulosa (TS), erythrokeratodermia variabilis (EKV), ichthyosis fetalis
(harlequin ichthyosis),
knuckle pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, squamous
cell carcinoma,
confluent and reticulated papillomatosis (CRP), acrochordons, cutaneous horn,
cowden disease
(multiple hamartoma syndrome), dermatosis papulosa nigra (DPN), epidermal
nevus syndrome
(ENS), ichthyosis vulgaris, molluscum contagiOsum, prurigo nodularis, and
acanthosis nigricans
(AN).
Examples of pulmonary disorders may include, but are not limited to, those
described in
U.S. publication no. 2005/0239842A1, published October27, 2005.
Specific examples may include pulmonary hypertension and related disorders.
Examples of
pulmonary hypertension and related disorders may include, but are not limited
to: primary pulmonary
hypertension (PPH); secondary pulmonary hypertension (SPH); familial PP11;
sporadic PPH;
precapillary pulmonary hypertension; pulmonary arterial hypertension (PAH);
pulmonary artery.
hypertension; idiopathic pulmonary hypertension; thrombotic pulmonary
arteriopathy (TPA);
plexogenic pulmonary arteriopathy; functional classes Ito IV pulmonary
hypertension; and
pulmonary hypertension associated with, related to, or secondary to, left
ventricular dysfunction,
mitral valvular disease, constrictive pericarditis, aortic stenosis,
cardiomyopathy, mediastinal
fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive
disease, collagen vasular
disease, congenital heart disease, HIV virus infection, drugs and toxins such
as fenfluramines,
congenital heart disease, pulmonary venous hypertension, chronic obstructive
pulmonary disease,
interstitial lung disease, sleep-disordered breathing, alveolar
hypoventilation disorder, chronic
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exposure to high altitude, neonatal lung disease, alveolar-capillary dysPluia,
sickle cell disease,
other coagulation disorder, chronic thromboemboll, connective tissue disease,
lupus including
systemic and Cutaneous lupus, schistosomiasis, sarcoidosis or pulmonary
capillary
hemangiomatosis.
Examples of asbestos-related disorders may include, but not limited to, those
described
In U.S. publication no. 2005/0100529, published May 12, 2005.
Specific examples may include, but are not limited to, mesothelioma,
asbestosis, malignant
pleural effusion, benign exudative effusion, pleural plaques, pleural
calcification, diffuse pleural
thickening, rounded atelectasis, fibrotic masses, and lung cancer.
Examples of parasitic diseases may include, but are not limited to, those
described in
U.S. publication no. 2006/0154880, published July 13, 2006.
Parasitic diseases may include diseases and disorders caused by human
intracellular parasites
such as, but not limited to, P. falcrarium, P. vale, P. vtvax, P. malartae,
L. donovart, L. infant urn,
L. aethlopka, L. major, L. troplea, L. mexicana, L. braziliensis, 7'. Gondii,
B. mkrod, B. divergens,
B. colt, C. parvum, C. cayekmensis, E. histolytica, I. belli, S. man:unit, S.
haematobium,
T'rypanosoma ssp.,.Toxoplasma ssp., and 0. volvu/us. Other diseases and
disorders caused by non-
human intracellular parasite such as, but not limited to, Babesia bovis,
Babesia cants, Banesta
Gibson', Besnaitia darling', Cpauxxoop felit, Elmeria ssp., Hammondia ssp.,
and Theileria ssp., may be
also encompassed. Specific examples may include, but are not limited to,
malaria, babesiosis,
= trypanosomiasis, leishmaniasis, toxoplasmosis, mcningoencephalitis,
keratitis, amebiasis, giardiasis,
cryptosporidiosis, isosporiasis; cyclosporiasis, microsporidiosis, ascariasis,
trichuriasis,
ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphatic
filariasis, onchocerciasis,
filariasis, schistosomiasis, and dermatitis caused by animal schistosomes.
Examples of immunodeficiendy disorders may include, but are not limited to,
those
described in U.S. publication no. 2006/0188475, published August 24, 2006.
Specific examples may
include, but not limited to, adenosine deaminase deficiency, antibody
deficiency with normal or
elevated Igs, ataxia-tenlangiectasia, bare lymphocyte syndrome, common
variable
immunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chain deletions, IgA
deficiency,
immunodeficiency with thymoma, reticular dysgenosis, Nezelof syndrome,
selective IgG subclass
deficiency, transient hypogammaglobulinemia of infancy, Wistcott-Aldrich
syndrome, X-linked
agammaglobulinemia, X-linked severe cornbined immunodeficiency.
Examples of CNS disorders may include, but are not limited to, those described
in U.S.
publication no. 2005/0143344, published June 30, 2005.
Specific examples may include, but are not limited to, Amyotrophic
Lateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington's Disease,
Multiple Sclerosis
other neuroimmunological disorders such as Toured Syndrome, delerium, or
disturbances in
consciousness that occur over a short period of time, and amnestic disorder,
or discreet memory
impairments that occur in the absence of Othet4central nervous system
impairments.
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Examples of CNS injuries and related syndromes may include, but are not
limited to,
those described in U.S. publication no. 2006/0122228, published June 8, 2000.
Specific examples may include, but are not limited to, CNS
injury/damage and related syndromes, including, but are not limited to,
primary brain injury,
secondary brain injury, traumatic brain injury, focal brain injury, diffuse
axonal injury, head injury,
concussion, post-concussion. syndrome, cerebral contusion and laceration,
subdural hematoma,
epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,
complete SCI, incomplete
SC!, acute SCI, subactite SCI, chronic SC!, central cord syndrome, Brown-
Sequard syndrome,
- . .
anterior cord syndrome, conus medullaris syndrome, cauda equine syndrome,
neurogenic shock,
spinal shock, altered level of consciousness, headache, nausea, emesis, memory
loss, dizziness,
diplopia, blurred vision, emotional lability, sleep disturbances,
irritability, inability to concentrate,
nervousness, behavioral impairment, cognitive deficit, and seizure.
Other disease or disorders may include, but not limited to, viral, genetic,
allergic, and
= autoimmune diseases. _Specific examples. may include, but not limited to,
HIV, hepatitis, adult
respiratory distress syndrome, bone resorption diseases, chronic pulmonary
inflammatory diseases,
dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,
hemodynamic shock, sepsis
syndrome, post ischemic reperfusion injury, meningitis, psoriasis, fibrotic
disease, cachexia, graft
versus host disease, graft rejection, auto-immune disease, rheumatoid
spondylitis, Crohn's disease,
ulcerative colitis, inflammatory-bowel disease, multiple sclerosis, systemic
lupus erythrematosus,
ENL in leprosy, radiatiotidamage, cancer, asthma, or hyperoxic alveolar
injury.
Examples of atherosclerosis and related conditions may include, but are not
limited to,
those disclosed inU.S. publication no. 2002/0054899, published May 9, 2002.
Specific examplesmay include, but are not limited to, various forms of
conditions
involving atherosclerosis, including r,estenosiw after vascular intervention
such as angioplasty,
stenting, atherectomy and grafting. Various forms of vascular intervention may
be contemplated herein,
including diseases of the cardiovascular and refilll system, such as, but not
limited to, renal
angioplasty, percutaneous coronary intervention (PCI), percutaneous
transluminal coronary
angioplasty (PTCA), carotid percutaneous transluminal angioplasty (PTA),
coronary by-pass
grafting, angioplasty with stent implantation, peripheral percutaneous
transluminal intervention of
the iliac, femoral or popliteal arteries, and surgical. intervention using
impregnated artificial grafts.
The following chart provides a listing of the major systemic arteries that may
be in need of
treatment:
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Artery Body Areas Supplied
Axillary = Shoulder and axilla
Brachial Upper arm
Brachiocephalic Head, neck, and arm
Celiac Divides into left gastric, splenic, and hepatic
arteries
Common carotid Neck
Common iliac Divides into external and internal iliac arteries
Coronary Heart
Deep femoral Thigh
Digital Fingers
Dorsalis pedis = Foot
External carotid Neck and external head regions
External iliac Femoral artery
Femoral Thigh
Gastric Stomach
Hepatic Liver, gallbladder, pancreas, and duodenum
Inferior mesenteric .. Descending colon, rectum, and pelvic wall
Internal carotid Neck and internal head regions
Internal iliac Rectum, urinary bladder, external genitalia,
buttocks muscles,
uterus and vagina
Left gastric Esophagus and stomach
Middle sacral Sacrum
Ovarian . -Ovaries
Palmar arch " Hand
Peroneal Calf
Popliteal Knee
Posterior tibial Calf =
Pulmonary Lungs
Radial Forearm
Renal Kidney
Splenic Stomach, pancreas, and spleen
Subclavian Shoulder
Superior mesenteric Pancreas, small intestine, ascending and
transverse colon
Testicular Testes
Ulnar Forearm
Examples of dysfunctional sleep and related syndromes may include, but are not
limited
to, those disclosed in U.S. publication no. 200510222209A1, published October
6,2005.
Specific examples may include, but are not limited to, snoring, sleep
apnea, insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleep
walking sleep eating, and
24

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= dysfunctional sleep associated with chronic neurological or inflammatory
conditions. Chronic
neurological or inflammatory conditions, include, but are not limited to,
Complex Regional Pain
Syndrome, chronic low back pain, musculoskeletal pain, arthritis,
mdiculopathy, pain associated
with cancer, flbrornyalgia, chronic fatigue syndrome, visceral pain, bladder
pain, chronic
pancreatitis, neuropathies (diabetic, post-herpetic, fraumaticõor
inflammatory), and
neurodegenemtive disorders such as Parkinson's Disease, Alzheimer's Disease,
tunyotrophic lateral
sclerosis, multiple sclerosis,.Huntington's Disease, bradylcinesia; muscle
rigidity; parkinsonian
tremor; parkinsonian gait; motion freezing; depression; defective long-term
memory, Rubinstein-
.
Taybi syndrome (TS); dementia; postural instability; hypokinetic disorders;
synuclein disorders;
multiple system atrophies; striatonigral degeneration; olivopontocerebellar
atrophy; Shy-Drager
= syndrome; motor neuron disease with parkinsonian features; Lowy body
dementia; Tau pathology
disorders; progressive supranuclear palsy; corticobasal degeneration;
frontotemporal dementia;
amyloid pathology disorders; mild cognitive impairment; Alzheimer disease with
parkinsonism;
Wilson disease; Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3
spinocembellar
ataxia; X-linked dyitonia parkinsonism; prion.disease; hyperkinetic disorders;
chorea; ballismus;
dystonia tremors; Arnyotrophic Lateral Sclerosis (ALS); CNS trauma and
myoclonus.
Examples of hemoglobinopathy and related disorders may include, but are not
limited to,
_those described in U.S.. publication no. 2005/0143420A1, published 'June
30,2005.
Specific examples may include, but are not limited to,
hemoglobinopatliy, sickle cell anemia, and any other disorders related to the
differentiation of '
CD34+ cells. =
Examples of 'TNFa related disorders may include, but are not limited to, those
described
in WO 98/03502 and WO 98/54170., both of which are incorporated herein in
their entireties by
reference. Specific examples may include, but are not limited to: endotoxemia
or toxic shock syndrome;
cachexia; adult respiratory distress syndrome; bone resorption diseases such
as arthritis;
hypercalcemia; Graft versus Host Reaction; cerebral Malaria; inflammation;
tumor growth; chronic
pulmonary inflammatory diseases; reperfusion injury; myocardial infarction;
stroke; circulatory
shock; rheumatoid arthritis; Crohn's disease; IAIV infection and AIDS; other
disorders such as
rheumatoid arthritis, rheumatoid spondylitis,.osteoarthritis, psoriatic
arthritis and other arthritic
conditions, septic shock, septis, endotcodc shock, graft versus host disease,
wasting, Crohn's disease,
ulcerative colitis, multiple sclerosis, systemic lupus erythromatosis, ENL in
leprosy, HIV, AIDS,
and opportunistic infections in AIDS; disorders such as septic shock, sepsis,
endotoxic shock,
hernodynamic shock and sepsis syndrome, post ischemic re' perfusion injury,
malaria, mycObacterial
infection, meningitis, psoriasis, congestive heart failure, fibrotic disease,
cachexia, graft rejection,
oncogenic or cancerous conditions, asthma, autoimmune disease, radiation
damages, and hyperoxic
alveolar injury; viral infections, such as those caused by the herpes viruses;
viral conjunctivitis; or
atopic dermatitis.
In other embodiments, the potential use of compounds provided herein in
various immunological applications such as vaccine adjuvants, including
anticancer vaccine
_
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CA 02704710 2015-07-07
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adjuvants, as disclosed in U.S. Publication No. 2007/0048327, published March
1, 2007,
may be also encompassed. These embodiments may also relate to the potential
uses of
compounds provided herein in combination with vaccines to treat or prevent
cancer or infectious
diseases, and other various potential uses of immunomodulatory compounds such
as reduction or
desensitization of allergic reactions.
Doses of a compound provided herein, or a pharmaceutically acceptable salt,
solvate, clathrate, stereolsomer or prodrug thereof, vary depending on factors
such as: specific
indication that may potentially be treated, prevented, or managed; age and
condition of a patient; and amount of
second active agept used, if any. generally, a compound provided herein, or a
pharmaceutically
acceptable salt, solvate, clathrate, stereoisomer or prodrug thereof, may be
used in an amount of
from about 0.1 mg to about 500 mg per day, and may be adjusted in a
conventional fashion (e.g., the
same amount administered each day of the treatment, prevention or management
period), in cycles
(e.g., one week on, one week off)i or in an amount that increases or decreases
over the course of
treatment, prevention, or management. In other embodiments, the dose may be
from about 1 mg to
about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg to about 200
mg, from about 10
mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg to about
50 mg, from
about 10 mg to abOut 5,0 mg, from about 20 mg to about 30 mg, or from about 1
mg to about 20 mg.
4.3 SECOND ACTWE AGENTS
A compound provided herein, or a pharmaceutically acceptable salt, solvate,
prodrug, clathrate, or stereoisomer thereof, may potentially be combined with
other pharmacologically active
compounds ("second active agents") in methods and compositions provided
herein. Certain
combinations may potentially work synergistically in the treatment of
particular types diseases or disorders, and
conditions and syMptoms associated with such diseases or disorders. A compound
provided herein,
or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomer or
prodrug thereof, may also potentially
work to alleviate adverse effects associated with certain second active
agents, and vice versa.
One or more second active ingredients or agents may potentially be used in the
methods and
compositions provided herein. Second active agents may be large molecules
(e.g., proteins) or small
molecules (e.g., synthetic inorganic, organometallic, or organic molecules).
Examples of large molecule active agents may include, but are not limited to,
hematopoietic.growth factors, cytokines, and monoclonal and polyclonal
antibodies. Specific
examples of the active agents are anti-CD40 monoclonal antibodies (such as,
for example, SGN-40);
histone deacetlyase inhibitors (such as, for example, SAHA and LAQ 824); heat-
shock protein-90
inhibitors (such as, for example, 17-AAG); insulin-like growth factor-I
receptor kinase inhibitors; =
vascular endothelial growth factor receptor kinase inhibitors (such as, for
example, PTK787); insulin
_
growth factor receptor inhibitors; lysophosphatidic acid acyltransrerase
inhibitors; IkB kinase
inhibitors; p38MAPK inhibitors; EGFR inhibitors (such as, for example,
gefitinib and erlotinib
HCL); HER-2 antibodies (such as, for example, trastuzumab (Herceptie) and
pertuzumab
(OmnitargTm)); VECIFR antibodies (such as, for example, bevacizumab
(AvastinTm)); VEGFR
26

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inhibitors (such as, for example, flk-1 specific kinase inhibitors, SU5416 and
ptk787/z1(222584);
P13K inhibitors (such as, for example, wortmannin); C-Met inhibitors (such as,
for example, PITA-
665752); monoclonal antibodies (such as, for example, rituximab (Rituxae),
tositumomab
(Bexxarl'), edrecolomab (Panoree) and G250); and anti-1NF-a antibodies.
Examples of small
molecule active agents may include, but are not limited to, anticancer agents
and antibiotics (e.g.,
clarithromycin).
Specific second active compounds that may potentially be combined with
compounds provided
herein vary depending on the specific indication that may potentially be
treated, prevented or managed.
For instance, for the potential treatment, prevention or management of cancer,
second active
agents may include, but are not limited to: semaxanib; cyclosporin;
etanercept; doxycycline; bortezomib;
acivicin; aclarubicin; acodazole hydrochloride;farcronine; adozelesin;
aldesleukin; altretamine;
ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;
asparaginase; asperlin;
azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide;
bisantrene hydrochloride;
bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium;
bropirimine; busulfan;
cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carrnustine;
carubicin
hydrochloride; carzelesin; c,edefingol; celecoxib; chlorambucil; cirolemycin;
cisplatin; cladribine;.
crisnatol mesylate; cyclophosphamide; cytambine; dacarbazine; dactinomycin;
daunorubicin
hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone;
docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene
citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride;
elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole;
esorubicin hydrochloride;
estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide
phosphate; etoprine;
fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine
phosphate; fluorouracil;
flurocitabine; fosquidone;.fostriecin Sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea;.
idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;
irinotecan hydrochloride;
lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride;
lometrexol sodium;
lomustine; losoxantrone hydrochloride; masoprocol; maytansine;
mechlorethamine,hydrochloride; .
megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;
methotrexate;
methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin;
mitocromin; mitogillin;
mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;
mycophenolic acid;
nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase;
peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;
piroxantrone
hydrochloride; plicamycin; plomestane.; porfimer sodium; porfiromycin;
prednimustine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol;
safingol hydrochloride; semustine; simtrazene; sparfoSate sodium; sparsomycin;
spirogermanium
hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;
sulofenur; talisomycin;
tecogalan sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin;
teniposide; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate;
trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate
glucuronate; triptorelin;
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tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin;
vinblastine sulfate;
vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;
vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate;
vorozole; zeniplatin; zinostatin;
and zorubicin hydrochloride.
Other second agents may include, but are not limited to: 20-epi-1,25
dihydroxyvitamin
D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;
adozelesin; aldesleukin;
ALL-TK antagonists; altretainine; ambamnstine; amidox; amifostine;
aminolevulinic acid;
amrubicin; amsacrine; anagrelIde; anastrozole; andrographolide; angiogenesis
inhibitors; antagonist
D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic
carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;
aphidicolin glycinate; apoptosis
gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase;
asulacrine; atamestane; atrimustine; axinastatin I; axinastatin 2; axinastatin
3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins;
benzoylstaurosporine; beta lactam derivativesvbeta-alethine; betaclamycin B;
betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;
bistratene A; bizelesin;
breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol;
calphostin C; camptothecin
derivatives; capecitabine; carboxamide-amino-triazole; carboxyarnidotriazole;
CaRest M3; CARN
700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine;
cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;
cis-porphyrin; cladribine;
clomifene analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4; combretastatin
analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin
A derivatives;
curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine
ocfosfate; cytolytic factor,
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide;
dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diplienyI spiromustine;
docetaxel; docosanol;
dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin
SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;
epirubicin; epristeride;
estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole;
etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim; flnasteride;
flavopiridol; flezelastine;
fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;
formestane; fostriecin;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;
gelatinase inhibitors;
gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin;
ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;
imatinib (Gleevee),
imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor
inhibitor; interferon
agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-
; iroplact;
irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F;
lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan
sulfate; leptolstatin; fetrozole;
leukemia inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone;
leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic
disaccharide peptide;
28

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine;
lometrexol; lonidamine;
losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine;
mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix
metalloproteinase
inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor;
mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin
analogues; mitonafide;
mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene;
molgramostim; Erbitux,
human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall
sk; mopidamol;
mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;
myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin;
naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;
nilutamide; nisamycin; nitric
oxide modulators; nitroxide antioxidant; nitrullyn; oblimersen (Genasense); 06-
benzylguanine;
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral
cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel;
paclitaxel analogues;
paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene;
parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate
sodium; pentostatin;
pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase
inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim;
placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum compounds;
platinum-triamine
complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone;
prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein kinase C
inhibitor; protein
kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors;
purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated
hemoglobin polyoxyethylene
conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras
inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186
etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl;
ruboxyl; safingol;
saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine;
senescence derived
inhibitor 1; sense oligonucleotides; signal transduction inhibitors;
sizofiran; sobuzoxane; sodium
borocaptate; sodium phenylacetate; solverol; somatomedin binding protein;
sonermin; sparfosic
acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine;
stipiamide; stromelysin
inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin;
swainsonine; tallimustine; tamoxifen methiodide; tauromustine; tazarotene;
tecogalan sodium;
tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide;
tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin
mimetic; thymalfasin;
thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin;
tirapazamine; titanocene bichloride; topsentin; toremifene; translation
inhibitors; tretinoin;
triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron;
turosteride; tyrosine kinase
inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived
growth inhibitory factor;
urokinase receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin;
29

CA 02704710 2015-07-07
=
=
53686-95
vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb;
and zinostatin
stimalamer.
Specific second active agents may include, but are not limited to, 2-
methoxyestradiol,
telomestatin, inducers of apoptosis in mutiple myeloma cells (such as, for
example, TRAIL), statins,
semaxanib, cyclosporin, etanercept, doxycycline, bortezomib, oblimersen
(Genasense), remicade,
docetaxel, celecoxib, melphrilan, dexamethhsone (Decadront, steroids,
gerncitabine, cisplatinum,
temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,
gliadel,
tamoxifen, topotecan, methotrexate, Arise, taxa', titxotere, fluorouracil,
leucovorin, irinotecan,
xeloda, CPT-11, interferon 'alpha, pegylated interferon alpha (e.g., PEG
INTRON-A), capecitabine,
cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol,
pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate,
biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,
doxorubicin (Doxilt,
paclitaxel, ganciclovir, adriamycin, estramustirie sodium phosphate (Emcytt,
sulindac, and
etoposide.
In another embodiment, examples of specific second agents according to the
indications that may potentially be treated, prevented, or managed may be
found in the following references
U.S. patent nos. 6,281,230 and 5,635,517; and U.S.
publication nos. 2004/0220144, 2004/0190609, 2004/0087546,
2005/0203142,2004/0091455,
2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880, 2006/0188475,
2006/0122228, and
2005/0143344.
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of pain may include, but are not limited to, conventional
therapeutics used to treat or
prevent pain such as antidepressants, anticonvulsants, antihypertensives,
anxiolytics, calcium
channel blockers, muscle relaxants, non-narcotic analgesics, opioid
analgesics, anti-inflammatories,
cox-2 inhibitors, immtinomodulatory agents, alpha-adrenergic receptor agonists
or antagonists,
immunosuppressive agents, corticosteroids, hyperbaric oxygen, ketamine, other
anesthetic agents,
NMDA antagonists, and other therapeutics found, for example, in the
Physician's Desk Reference
2003. Specific examples may include, but are not limited to, salicylic acid
acetate (Aspirin ), celecoxib
(Celebrext, Enbrel4D, ketamine, gabapentin (Neurontint, phenytoin (Dilantint,
carbamazepine
(Tegretolt, oxcarbazepine (Trileptalt, valproic acid (Depakene), morphine
sulfate,
hydromorphone, prednisone, griseofulvin, penthonium, alendronate,
dyphenhydramide,
guanethidine, ketorolac (Acular), thyrocalcitonin, dimethylsulfoxide (DMSO),
clonidine
(Catapress), bretylium, ketanserin, reserpine, droperidol, atropine,
phentolamine, bupivacaine,
lidocaine, acetaminophen, nortriptyline (Pamela?), amitriptyline imipramine
(Tofranilt,
doxepin (Sinequan), clomipramine (Anafranilt, fluoxetine (Frazee), sertraline
(Zoloftt,
naproxen, nefazodone (Serzone), venlafaxine (Effexor.), trazodone (Desyrelt,
bupropion
(Wellbutrint, mexiletine, nifedipine, propranolol, tramadol, lamotrigine,
vioxx, ziconotide,
ketamine, dextromethorphan, benzodiazepines, bactofen, tizanidine and
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Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of macular degeneration and related syndromes may include,
but are not limited to, a
steroid, a light sensitizer, an integrin, an antioxidant, an interferon, a
xanthine derivative, a growth
hormone, a neutrotrophic factor, a regulator, of neovascularization, an anti-
VEGF antibody, a
prostaglandin, an antibiotic, a phytoestrogen, an anti-inflammatory compound
or an
antianglogenesis compound, or a combination thereof. Specific examples may
include, but are not
limited to, verteporfin, purlytin, an angiostatic steroid, rhuFab, interferon-
2a, pentoxifylline, tin
etiopurpurin, motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,
17-1-methylethylkdinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost (see
U.S. Patent No.
6,225,348), tetracycline and its derivatives, rifamycin and its derivatives,
macrolides, metronidazole
(U.S. Patent Nos. 6,218,369 and 6,015,803), genistein, genistin, 6'-0-Mal
genistin, 6'-0-Ac
genistin, daidzein, daidzin, 6'-O-Mal daidzin, 6'-0-Ac daidzin, glycitein,
glycitin, 6'-O-Mal
glycitin, biochanin A, formononetin (U.S. Patent No. 6,001,368), triamcinolone
acetomide,
dexamethasone (U.S. Patent No. 5,770,589), thalidomide, glutathione (U.S.
Patent No. 5,632,984),
basic fibroblast growth factiir (bFGF), transforming growth factor b (TGF-b),
brain-derived
neurotrophic factor (BDNF), plasminogen activator factor type 2 (PAI-2),
EYE101 (Eyetech
Pharmaceuticals), LY3,33531 (Eli Lilly), Miravant, and RET1SERT implant
(Bausch & Lomb).
= =
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of skin diseases may include, but are not limited to,
keratOlytics, retinoids, a-hydroxy
acids, antibiotics, c011agen, botulintnn toxin, interferon, steroids, and
irnmunomodulatory agents.
Specific examples may include, but are not limited to, 5-fluorouracil,
masoprocol, trichloroacetic acid,
salicylic acid, lactic acid, anutumium lactate, urea, tretinoin, isotretinoin,
antibiotics, collagen,
botulinum toxin, interferon, corticosteroid, transretipoic acid and collagens
such as human placental
collagen, animal placental collagen, Derinalogen, AlloDerm, Fascia, Cymetra,
Autologen, Zyderm,
Zyplast, Resoplast, and Isolagen.
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of pulmonary hepertension and related disorders may include,
but are not limited to,
anticoagulants, diuretics, cardiac glycosides, calcium channel blockers,
vasodilators, prostacyclin
analogues, endothelin antagonists, phosphodiesterase inhibitors (e.g., PDE V
inhibitors),
endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors, and
other therapeutics
known to reduce pulmonary artery pressure. Specific examples may include, but
are not limited to,
warfarin (Coumadie), a diuretic, a cardiac glycoside, digoxirpoxygen,
diltiazem, nifedipine, a
vasodilator such as prostacyclin (e.g., prostaglandin 12 (P012), epoprostenol
(EPO, Florantl.),
treprostinil (Remoduline), nitric oxide (NO), bosentan (Tracleere),
amlodipine, epoprostenol
(Floranc), treprostinil (Remodulie), prostacyclin, tadalafil
simvastatin (Zocoiv), =
omapatrilat (Vanlevq), irbesartan (Avapre), pravastatin (Pravacholl"),
digoxin, L-arginine, iloprost,
betaprost, and sildenafil (Viagre).
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Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of asbestos-related disordin may include, but are not
limited to, anthracycline,
' platinum, alkylating agent, oblimersen (Genasefisee), cisplatinum,
cyclophosphamide, temodar,
= carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,
taxotere, irinotecan,
capecitabine, cisplatin, thiotepd, fludarabine, carboplatin, liposomal
daunorubicin, cytarabine,
doxetaxol, pacilitaxel, vinblastine, 1L-2, GM-CSF, dacarbazine, vinorelbine,
zoledronic acid,
palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine,
doxorubicin (Doxile), paclitaxel, ganciclovir, adriamycin, bleomycin,
hyaluronidase, mitomycin C,
mepacrine, thiotepa, tetracyaline and gemcitabine.
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of parasitic diseases may include, but are not limited to,
chloroquine, quinine,
quinidine, pyrimethamine, sulfadiazine, doxycycline, clindamycin, mefloquine,
halofantrine,
primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin, surarnin,
pentamidine,
melarsoprol, nifurtimox, benznidazole, amphotericin B, pentavalent antimony
compounds (e.g.,
sodium stiboglucuronate), interfereon gamma, itraconazole, a combination of
dead promastigotes
and BCG, leucovorin, corticosteroids, sulfonamide, spiramycin, IgG (serology),
trimethoprim, and
sulfamethoxazole.
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of immunodeficiency disorders may include, but are not
limited to: antibiotics
(therapeutic or prophylactic) such as, but not limited to, ampicillin,
tetracycline, penicillin,
cephalosporins, streptomycin, kanamycin, and erythromycin; antivirals such as,
but not limited to,
amantadine, rimantadine, acyclovir, and ribavirin; immunoglobulin; plasma;
immunologic
enhancing drugs such as, but not limited to; levami sole and isoprinosine;
biologics such as, but not
limited to, gammaglobulin, transfer factor, interleukins, and interferons;
hormones such as, but not
limited to, thymic; and other immunologic agents such as, but not limited to,
B cell stimulators (e.g.,
BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growth factors (e.g., TGF-
a), antibodies (e.g.,
anti-CD40 and IgM), oligonucleotides containing unmethylated CpG motifs, and
vaccines (e.g.,
vjral and tumor peptide vaccines).
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of CNS disorders may include, but are not limited to:
opioids; an dopamine agonist or
antagonist, such as, but not limited to, Levodopa, L-DOPA, cocaine, a-methyl-
tyrosine, reserpine,
tetrabenazine, benzon-opine, pargyline, fenodolpam mesylate, cabergoline,
pramipexole
dihydrochloride, ropinorole, amantinline hydrochloride, selegiline
hydrochloride, carbidopa,
pergolide mesylate, Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but
not limited to,
iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor, such
as, but not limited to,
tolcapone and entacapone; a cholinesterase inhibitor, such as, but not limited
to, physostigmine
saliclate, physostigmine sulfnte, physostigmine bromide, meostigmine bromide,
neostigmine
methylsulfate, ambenonim chloride, edrophonium chloride, tacrine, pralidoxime
chloride,
obidoxime chloride, trimedoxime bromide, diacetyl monoxim, endrophonium,
pyridostigmine, and
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demecarium; an anti-inflammatory agent, such as, but hot limited to, naproxen
sodium, diclofenac
sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin, diflunisal,
etodolac, meloxicam,
ibuprofen, ketoprofen, nabumetone, refecoxib, methottexate, leflunomide,
sulfasalazine, gold salts,
Rho-D Immune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,
tacrolimus,
basiliximab, daclizumab, salicylic acid, acetylsalicylic acid, methyl
salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic
acid, meclofenamate
sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam,
meloxicam,
ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone,
antipyrine,
aminopyrine, apazone, zileuton, aurothioglucose, gold sodium thiomalate,
auranofin, methotrexate,
colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone or
betamethasone and other
glucocorticoids; and an antiemetic agent, such as, but not limited to,
metoclopromide, domperidone,
prochlorperazine, promethaiine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron,
hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine,
bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,
dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine,
sulpiride,
tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron, and a
mixture thereof.
Examples of second active agents that may be,used for the potential treatment,
prevention
and/or management of CNS injuries and related syndromes may include, but are
not limited to,
immunomodulatory agents, immunosuppressiye agents, antihypertensives,
anticonvulsants,
fibrinolytic agents, antiplatelet agents, antipsychotics, antidepressants,
benzediazepines, buspirone,
amantadine, and other known or conventional agents used in patients with CNS
injury/damage and
related syndromes. Specific examples may include, but are not limited to:
steroids (e.g., glucocorticoids,
such as, but not limited to, methylprednisolone, dexamethasone and
betarnethasone); an anti-
inflammatory agent, including, but not limited to, naproxen sodium, diclofenac
sodium, diclofenac
potassium, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,
ibuprofen, ketoprofen,
nabumetone, refecoxib, methotrexate, leflupomide, sulfasalazine, gold salts,
RHo-D Immune
Globulin, mycophenylate mofetil, cyclosporine, azathioprine, tacrolimus,
basiliximab, daclizumab,
salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,
salsalate, olsalazine, sulfasalazine,
acetaminophen, indomethacin, sulindac, mefenamic acid, meclofenamate sodium,
tolmetin,
ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,
ampiroxicam, droxicam,
pivoxicam, tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine,
aminopyrine, apazone,
zileuton, aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,
colchicine, allopurinol,
probenecid, sulfinpyrazone and benzbromarone; a cAMP analog including, but not
limited to, db-
cAMP; an agent comprising a methylphenidate drug, which comprises l-threo-
methylphenidate, d-
threo-methylphenidate, dl-threo-methylphenidate, l-erythro-methylphenidate, d-
erythro-
methylphenidate, dl-erythro-methylphenidate, and a mixture thereof; and a
diuretic agent such as,
but not limited to, mannitol, fiirosemide, glycerol, and urea.
Examples of second active agent that may be used for the potential treatment,
prevention
and/or management of dysfunctional sleep and related syndromes may include,
but are not limited to, a
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tricyclic antidepressant agent, a selective serotonin reuptal.e. inhibitor, an
antiepileptic agent
(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,
topiramate), an antiaryhthmic
agent, a sodium channel blocking agent, a selective inflammatory mediator
inhibitor, an opioid
agent, a second immunomodulatory compound, a combination agent, and other
known or
conventional agents used in sleep therapy., Specific examples may include, but
are not limited to,
Neurontin, oxycontin, morphine, topiramate; amitryptiline, ndrtryptiline,
carbamazepine, Levodopa,
L-DOPA, cocaine, a-methyl-tyrosine, reserpine, tetrabenazine, benzotropine,
pargyline, fenodolpam
mesylate, cabergoline, pramipexole dihydrochloride, ropinorole, amantadine
hydrochloride,
selegiline hydrochloride, carbidopa, pergolide mesylate, Sinemet CR,
Symmetrel, iproniazid,
clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone, physostigmine
saliclate,
physostigmine sulfate, physostigmine bromide, meostigmine bromide, neostigmine
methylsulfate,
ambenonim chloride, edrophonium chloride, tacrine, pralidoxime chloride,
obidoxime chloride,
trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigrnine,
demecarium, naproxen
sodium, diclofenac sodium, diclofenac potassium, celecoxib, sulindac,
oxaprozin, diflunisal,
etodolac, meloxicam, ibupreen, ketoprofen, nabumetone, refecoxib,
methotrexate, leflunomide,
sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,
cyclosporine,
azathioprine, tacrolimus, basiliximab, daclizumab, salicylic acid,
acetylsalicylic acid, methyl
salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen,
indomethacin, sulindac,
mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac,
flurbinprofen, oxaprozin,
piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam,
phenylbutaame,
oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton, aurothioglucose,
gold sodium
thiomalate, auranofin, methotrexate, colchicine, allopurinol, probenecid,
sulfinpyrazone,
benzbromarone, betamethasone and other glucocorticoids, metoclopromide,
domperidone,
prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,
ondansetron, granisetron,
hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine,
bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,
dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine,
sulpiride,
tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisen-on, and a
mixture thereof.
Examples of second active agents that may be used for the potential treatment,
prevention
and/or management of hemoglobinopathy and related disorders may include, but
are not limited to:
interleukins, such as IL-2 (including recombinant IL-II ("rIU') and canarypox
IL-2), IL-10, IL-12,
and IL-18; interferons, such as interferon alfa-2a, interferon alfa-2b,
interferon alfa-nl, interferon
alfa-n3, interferon beta-I a, and interferon gamma-I b; and G-CSF;
hydroxyurea; butyrates or
butyrate derivatives; nitrous oxide; hydroxy urea; HEMOXINT" (NIPRISANT"; see
United States
Patent No. 5,800,819); Gardos channel antagonists such as clotrimazole and
triaryl methane
derivatives; Deferoxamine; protein C; and transfusions of blood, or of a blood
substitute such as
HemospanTM or HemospanTm PS (Sangart).
Administration of a compound provided herein, or a pharmaceutically acceptable

salt, solvate, clathrate, stemoisomer or prodrug thereof, and the second
active agents to a patient may
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occur simultaneously or sequentially by the same or different routes of
administration. The
suitability of a particular route of administration employed for a particular
active agent will
depend on the active agent itself (e.g., whether it can be administered orally
without
decomposing prior to entering the blood stream) and the disease that may
potentially be
treated. One of administration for compounds provided herein is oral. Routes
of
administration for the second active agents or ingredients are known to those
of ordinary skill
in the art. See, e.g., Physicians' Desk Reference (60th ed., 2006).
In one embodiment, the second active agent may be administered intravenously
or subcutaneously and once or twice daily in an amount of from about 1 to
about 1000 mg,
from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50
to about
200 mg. The specific amount of the second active agent will depend on the
specific agent
used, the type of disease that may potentially be treated or managed, the
severity and stage of
disease, and the amount(s) of compounds provided herein and any optional
additional active
agents concurrently administered to the patient.
As discussed elsewhere herein, also encompassed is a method that may
potentially reduce, treat and/or prevent adverse or undesired effects
associated with
conventional therapy including, but not limited to, surgery, chemotherapy,
radiation therapy,
hormonal therapy, biological therapy and immunotherapy. Compounds provided
herein and
other active ingredients may potentially be administered to a patient prior
to, during, or after
the occurrence of the adverse effect associated with conventional therapy.
4.4 Cycling Therapy
In certain embodiments, the prophylactic or therapeutic agents provided herein

may potentially be cyclically administered to a patient. Cycling therapy
involves the
administration of an active agent for a period of time, followed by a rest (L
e., discontinuation
of the administration) for a period of time, and repeating this sequential
administration.
Cycling therapy may potentially reduce the development of resistance to one or
more of the
therapies, avoid or reduce the side effects of one of the therapies, and/or
improve the efficacy
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Consequently, in one embodiment, a compound provided herein may be
administered daily in a single or divided doses in a four to six week cycle
with a rest period of
about a week or two weeks. Cycling therapy may further allow the frequency,
number, and
length of dosing cycles to be increased. Thus, in another embodiment, a
compound provided
herein may be administered for more cycles than are typical when it is
administered alone. In
yet another embodiment, a compound provided herein may be administered for a
greater
number of cycles than would typically cause dose-limiting toxicity in a
patient to whom a
second active ingredient is not also being administered.
In one embodiment, a compound provided herein may be administered daily
and continuously for three or four weeks at a dose of from about 0.1 mg to
about 500 mg per
day, followed by a rest of one or two weeks. In other embodiments, the dose
may be from
about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg, from about 1 mg
to about
200 mg, from about 10 mg to about 100 mg, from about 0.1 mg to about 50 mg,
from
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about 10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about I
mg to about 20 mg,
followed by a rest.
In one embodiment, a compound provided herein and a second active ingredient
may be
administered orally, with administration of the compound provided herein
occurring 30 to 60
minutes prior to the second active ingredient, dpring a cycle of four to six
weeks. In another
embodiment, the combination of a compound provided herein and a second active
ingredient may be
administered by intravenous infusion over about 90 minutes every cycle.
Typically, the number of cycles during which the potential combination
treatment is
administered to a patient will be from about one to about 24 cyclts, from
about two to about 16
cycles, or from about four to about three cycles.
4.5 PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
Pharmaceutical compositions can be used in the preparation of individual,
single
unit dosage forms. Pharmaceutical compositions and dosage forms provided
herein comprise a
compound provided herein, or a pharmaceutically acceptable salt, solvate,
stereoisomer, clathrate, or
prodrug thereof. Pharmaceutical compositions and dosage forms can further
comprise one or more
excipients.
Pharmaceutical compositions, and dosage forms provided herein can also
comprise
one or more additional active ingredients. Examples of optional second, or
additional, active
ingredients are disclosed in Section 4.3, above.
Single unit dosage forms provided herein are suitable for oral, mucosal (e.g.,
nasal,
sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous,
intravenous, bolus injection,
intramuscular, or intraarterial), topical (e.g., eye drops or other ophthalmic
preparations),
transdermal or transcutaneous administration to a patient. Examples of dosage
forms include, but
are not limited to: tablets; caplets; capsules, such as soft elastic gelatin
capsules; cachets; troches;
lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or
inhalers); gels; liquid
dosage forms suitable for oral or mucosal administration to a patient,
including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-
in-oil liquid
emulsions), solutions, and elixirs; liquid dosage forms suitable for
parenteral administration to a
patient; eye drops or other ophthalmic preparations suitable for topical
administration; and sterile
solids (e.g., crystalline or amorphous solids) that can be reconstituted to
provide liquid dosage forms
suitable for parenteral administration to a patient.
The composition, shape, and type of dosage forms will typically vary depending
on
their use. For example, a dosage form used in the acute treatment of a disease
may contain larger
amounts of one or more of the active ingredients it comprises than a dosage
form used in the chronic
treatment of the same disease. Similarly, a parenteral dosage form may contain
smaller amounts of
one or more of the active ingredients it comprises than an oral dosage form
used to treat the same
disease. These and other ways in which specific dosage forms are used will
vary from one another
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will be readily apparent to those skilled in the art. See, e.g., Remington's
Pharmaceutical Sciences,
18th ed., Mack Publishing, Easton PA (1990).
In one embodiment, pharmaceutical compositions and dosage forms comprise one
or more excipients. Suitable excipients are well known to those skilled in the
art of pharmacy, and
non-limiting examples of suitable excipients are provided herein. Whether a
particular excipient is
suitable for incorporation into a pharmaceutical composition or dosage form
depends on a variety of
factors well known in the art including, but not limited to, the way in which
the dosage form will be
administered to a patient. For example, oral dosage forms such as tablets may
contain excipients not
suited for use in parenteral dosage forms. The suitability of a particular
excipient may also depend
on the specific active ingredients in the dosage form. For example, the
decomposition of some
active ingredients may be accelerated by some excipients such as lactose, or
when exposed to water.
Active ingredients that comprise primary or secondary amines are particularly
susceptible to such
accelerated decomposition. Consequently, provided are pharmaceutical
compositions and dosage
forms that contain little, if any, lactose, or other mono- or di-saccharides.
As used herein, the term
"lactose-free" means that the amount of lactose present, if any, is
insufficient to substantially
increase the degradation rate of an active ingredient.
Lactose-free compositions can comprise excipients that are well known in the
art
and are listed, for example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In
general, lactose-
free compositions comprise active ingredients, a binder/filler, and a
lubricant in pharmaceutically
compatible and pharmaceutically acceptable amounts. In one embodiment, lactose-
free dosage
forms comprise active ingredients, microcrystAlline cellulose, pre-gelatinized
starch, and magnesium
stearate.
Also provided are anhydrous pharmaceutical compositions and dosage forms
comprising active ingredients, since water can facilitate the degradation of
some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of
simulating long-term storage in order to determine characteristics such as
shelf-life or the stability of
formulations overtime. See, e.g., Jens T. Carstensen, Drug Stability:
Principles & Practice, 2d.
Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and heat
accelerate the
decomposition of some compounds. Thus, the effect of water on a formulation
can be of great
significance since moisture and/or humidity are commonly encountered during
manufacture,
handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms can be prepared using
anhydrous or low moisture containing ingredients and low moisture or low
humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose and at
least one active
ingredient that comprises a primary or secondary amine are preferably
anhydrous if substantial
contact with moisture and/or humidity during manufacturing, packaging, and/or
storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such
that
its anhydrous nature is maintained. Accordingly, anhydrous compositions are,
in one embodiment,
packaged using materials known to prevent exposure to water such that they can
be included in
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suitable formulary kits. Examples of suitable packaging include, but are not
limited to, hermetically
sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
Also provided are pharmaceutical compositions and dosage forms that comprise
one
or more compounds that reduce the rate by which an active ingredient will
decompose. Such
compounds, which are referred to herein as "stabilizers," include, but are not
limited to, antioxidants
such as ascorbic acid, pI-1 buffers, or salt buffers.
Like the amounts and types of excipients, the amounts and specific types of
active
ingredients in a dosage form may differ depending on factors such as, but not
limited to, the route by
which it is to be administered to patients. In one embodiment, dosage forms
comprise a compound
provided herein in an amount of from about 0.1P to about 500 mg. In other
embodiments, dosage
forms comprise a compound provided herein in an amount of about 0.1, 1, 2, 5,
7.5, 10, 12.5, 15,
17.5, 20, 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
In other embodiments, dosage forms comprise the second active ingredient in an
amount of 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to
about 350 mg, or
from about 50 to about 200 mg. Of course, the specific amount of the second_
active agent will
depend on the specific agent used, the diseases or disorders that may
potentially be treated or managed, and the
amount(s) of a compound provided herein, and any optional additional active
agents concurrently
administered to the patient.
4.5.1 ORAL DOSAGE FORMS
Pharmaceutical compositions that are suitable for oral administration can be
provided as discrete dosage, forms, such as, but not limited to, tablets
(e.g., chewable tablets),
caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms
contain predetermined
amounts of active ingredients, and may be prepared by methods of pharmacy well
known to those
skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th
ed., Mack Publishing,
Easton PA (1990).
Oral dosage forms provided herein are prepared by combining the active
ingredients
in an intimate admixture with at least one excipient according to conventional
pharmaceutical
compounding techniques. Excipients can take a wide variety of forms depending
on the form of
preparation desired for administration. For example, excipients suitable for
use in oral liquid or
aerosol dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents,
preservatives, and coloring agents. Examples of excipients suitable for use in
solid oral dosage
forms (e.g., powders, tablets, capsules, and caplets) include, but are not
limited to, starches, sugars,
micro-crystalline cellulose, diluents, granulating agents, lubricants,
binders, and disintegrating
agents.
In one embodiment, oral dosage forms are tablets or capsules, in which case
solid
excipients are employed. In another embodiment, tablets can be coated by
standard aqueous or
nonaqueous techniques. Such dosage forms can be prepared by any of the methods
of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared by
uniformly and intimately
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WO 2009/042177 PCT/US2008/011124
admixing the active ingredients with liquid carriers, finely divided solid
carriers, or both, and then
shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed
tablets can be prepared by compressing in a suitable machine the active
ingredients in a free-flowing
form such as powder or granules, optionally mixed with an excipient. Molded
tablets can be made
by molding in a suitable machine a mixture of the powdered compound moistened
with an inert
liquid diluent.
Examples of excipients that can be used in oral dosage forms provided herein
include, but are not limited to, binders, fillers, disintegrants, and
lubricants. Binders suitable for use
in pharmaceutical compositions and dosage forms include, but are not limited
to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such as acacia,
sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and its
derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium
carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl
methyl cellulose,
(e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures
thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to,
the
materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105
(available from FMC Corporation, American Viscose Division, Avicel Sales,
Marcus Hook, PA),
and mixtures thereof. An specific binder is a mixture of microcrystalline
cellulose and sodium
carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low
moisture excipients
or additives include AVICELPH103TM and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and
dosage
forms provided herein include, but are not limited to, talc, calcium carbonate
(e.g., granules or
powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid,
sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or
filler in pharmaceutical
compositions is, in one embodiment, present in from about 50 to about 99
weight percent of the
pharmaceutical composition or dosage form.
Disintegrants may be used in the compositions to provide tablets that
disintegrate when exposed to
an aqueous environment. Tablets that contain too much disintegrant may
disintegrate in storage,
while those that contain too little may not disintegrate at a desired rate or
under the desired
conditions. Thus, a sufficient amount of disintegrant that is neither too much
nor too little to
detrimentally alter the release of the active ingredients may be used to form
solid oral dosage forms.
The amount of disintegrant used varies based upon the type of formulation, and
is readily discernible
to those of ordinary skill in the art. In one embodiment, pharmaceutical
compositions comprise
from about 0.5 to about 15 weight percent of disintegrant, or from about 1 to
about 5 weight percent
of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms

include, but are not limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose,
croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch
glycolate, potato or
39

CA 02704710 2015-07-07
53686-95
tapioca starch, other starches, pre-gelatinized starch, other starches, clays,
other algins, other
celluloses, gums, and mixtures thereof. -
Lubricants that can be used in pharmaceutical compositions and dosage forms
include, but are not limited to, calcium stearate, magnesium stearate, mineral
oil, light mineral oil,
glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic
acid, sodium lauryl sulfate,
talc, hydrogenated vegetable oil (e.g.; peanut oil, cottonseed oil, sunflower
oil, sesame oil, olive oil,
corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar.
and mixtures thereof.
TM
Additional lubricants include, for example, a syloid silica gel (AEROS1L200,
manufactured by W.R.
Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica
(marketed by Degussa Co. of
Plano, TX), CAB-0-SIL (a pyrogenic silicen dioxide product sold by Cabot Co.
of Boston, MA),
and mixtures thereof. If used at all, lubricants may be used in an amount of
less than about 1 weight
percent of the pharmaceutical compositions or dosage forms into which they are
incorporated.
In one embodiment, a solid oral dosage form comprises a compound provided
herein, anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone,
ste-aric acid, colloidal
anhydrous silica, and gelatin.
4.5.2 CONTROLLED RELEASE DOSAGE FORMS
Active ingredients provided herein can be administered by controlled release
means
or by delivery devices that are well known to those of ordinary skill in the
art. Examples include,
but are not limited to, those described in U.S. Patent Nos.: 3,845,770;
3,916,899; 3,536,809;
3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,
5,073,543, 5,639,476,
5,354,556, and 5,733,566,Such dosage forms
can be used to provide slow or controlled-release of one or more active
ingredients using, for
example, hydropropylmethyl celluhise, other p9Iymer matrices, gels, permeable
membranes,
osmotic systems, multilayer coatings, mieroparticles, liposomes, microspheres,
or a cbmbinatiop
thereof to provide thedesired release profile in varying proportions. Suitable
controlled-release
formulations known to those of ordinary skill in the art, including those
described herein, can be
readily selected for use with the active agents provided herein. In one
embodiment, provided are
single unit dosage forms suitable for oral administration such as, but not
limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
In one embodiment, controlled-release pharmaceutical products may potentially
improve drug
therapy over that achieved by their non controlled counterparts. In another
embodiment, the use of
a controlled-release preparation in medical treatment is characterized by a
minimum of drug
substance being employed to cure or control the condition in a minimum amount
of time.
Advantages of controlled-release formulations may include extended activity of
the drug, reduced dosage
frequency, and increased patient compliance. In addition, controlled-release
formulations may be
used to affect the time of onset of action or other characteristics, such as
blood levels of the drug,
and can thus affect the occurrence of side ke.g., adverse) effects.

CA 02704710 2015-07-07
53686-95
In another embodiment, the controlled-release formulations are designed to
initially
release an amount of drug (active ingredient) that promptly produces the
desired therapeutic or
prophylactic effect, and gradually and continually release of other amounts of
drug to maintain this
level of therapeutic or prophylactic effect over an extended period of time.
In one embodiment, in
order to maintain a constant level of drug in the body, the drug can be
released from the dosage form
at a rate that will replace the amount of drug being metabolized and excreted
from the body.
Controlled-release of an active ingredient can be stimulated by various
conditions including, but not
limited to, pH, temperature, enzymes, water, or other physiological conditions
or compounds.
4.5.3 PARENTERAL DOSAGE FORMS
Parenteral dosage forms can be administered to patients by various routes
including,
but not limited to, subcutaneous, intravenous (including bolus injection),
intramuscular, and
intraarterial. In some embodiments, administration of a parenteral dosage form
bypasses patients'
natural defenses against contaminants, and thus, in these embodiments,
parenteral dosage forms are
sterile or capable of being sterilized prior to administration to a patient.
Examples of parenteral
dosage forms include, but are not limited to, solutions ready for injection,
dry products ready to be
dissolved or suspended in a pharmaceutically acceptable vehicle for injection,
suspensions ready for
injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms are well

known to those skilled in the art. Examples include, but are not limited to:
Water for Injection
USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated
Ringer's Injection; water-
miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene
glycol, and polypropylene
glycol; and non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil,
sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
Compounds that increase the solubility of one or more of the active
ingredients
disclosed herein can also be incorporated into the parenteral dosage forms.
For example,
cyclodextrin and its derivatives may be used to potentially increase the
solubility of a compound provided
herein. See, e.g., U.S. Patent No. 5,134,127, Which is incorporated herein by
reference.
4.5.4 TOPICAL AND MUCOSAL DOSAGE FORMS
Topical and mucosaf dosage forms provided herein include, but are not limited
to,
sprays, aerosols, solutions, einulsions, suspensions, eye drops or other
ophthalmic preparations, or
other forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16th
and 18th eds., Mack Publishing, Easton PA (1980 & 1990); and Introduction to
Pharmaceutical
Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms
suitable for treating .
mucosal tissues within the oral cavity can be formulated as mouthwashes or as
oral gels.
Suitable excipients (e.g., carriers and diluents) and other materials that can
be used
to provide topical and mucosal dosage forms encompassed herein are well known
to those skilled in
41

CA 02704710 2015-07-07
53686-95
the pharmaceutical arts, and depend on the particular tissue to which a given
pharmaceutical
composition or dosage form will be applied. In one embodiment, excipients
include, but are not
limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-
1,3-diol, isopropyl
myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form
solutions, emulsions or
gels, which are non-toxic and pharmaceutically acceptable. Moisturizers or
humectants can also be
added to pharmaceutical compositions and dosage forms. Examples of additional
ingredients are
well known in the art. See, e.g., Remington's Pharmaceutical Sciences, 16th
and 18th eds., Mack
Publishing, Easton PA (1980 & 1990).
The pH of a pharmaceutical composition or dosage form may also be adjusted to
improve delivery of one or more active ingredients. Also, the polarity of a
solvent carrier, its ionic
strength, or tonicity can be adjusted to improve delivery. Compounds such as
stearates can also be
added to pharmaceutical compositions or dosage forms to alter the
hydrophilicity or lipophilicity of
one or more active ingredients so as to improve delivery. In other
embodiments, stearates can serve
as a lipid vehicle for the formulation, as an emulsifying agent or surfactant,
or as a delivery-
enhancing or penetration-enhancing agent. In other embodiments, salts,
solvates, prodrugs,
clathrates, or stereoisomers of the active ingredients can be used to further
adjust the properties of
the resulting composition.
4.6 KITS
In one embodiment, active ingredients provided herein are not administered to
a
subject at the same time or by the same route of administration. In another
embodiment, provided
are kits which can simplify the administration of appropriate amounts of
active ingredients.
In one embodiment, a kit comprises a dosage form of a compound provided
herein.
Kits can further comprise additional active ingredients such as oblimersen
(Genasense), melphalan,
G-CSF, GM-CSF, EPO, topotecan, dacarbazine, irinoteean, taxotere, 1FN, COX-2
inhibitor,
pentoxifylline, ciprofloxacin, dexamethasone, 1L2, 11.8, 11,18, Ara-C,
vinorelbine, isottetinoin, 13
cis-retinoic acid, or a pharmacologically active, mutant or derivative
thereof, or a combination
thereof. Examples of the additional active ingredients include, but are not
limited to, those disclosed
herein (see, e.g., section 4.3).
In other embodiments, kits can further comprise devices that are used to
administer
the active ingredients. Examples of such devices include, but are not limited
to, syringes, drip bags,
patches, and inhalers.
Kits can further comprise cells or blood for transplantation as well as
pharmaceutically acceptable,vehicles that can be used to administer one or
more active ingredients.
For example, if an active ingredient is provided in a solid form that must be
reconstituted for
parenteral administration, the kit can comprise a sealed container of a
suitable vehicle in which the
active ingredient can be dissolved to form a particulate-free sterile solution
that is suitable for
parenteral administration. Examples of pharmaceutically acceptable vehicles
include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but not limited
to, Sodium Chloride
42

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but not limited
to, ethyl alcohol,
polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such
as, but not limited to,
corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl
benzoate.
5. EXAMPLES
Certain embodiments of the invention are illustrated by the following non-
limiting
examples.
5.1 3-(2,6-DEVIETHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERLDINE-2,6-
DIONE
0 0 N 0
op,
To a stirred mixture of 2-amino-5-methylbenzoic acid (4.8 g, 32 mmol) and
imidazole (2.6 g, 38 mmol) in acetonitrile (100 mL), was added acetyl chloride
(2.7 mL, 38 mmol)
at room temperature. The Mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (5.2 g, 32 mmol),
imidazole (4.7 g, 70
mmol) and triphenyl phosphite (9.9 mL, 38 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (100 mL). The suspension was filtered and washed with
water (2 X 100
mL), ethyl acetate (2 X 100 mL), sodium hydrogen carbonate (sat, 100 mL) and
water (100 mL) to
give a white solid, which was stirred in DMF (40 mL) overnight. The suspension
was filtered and
washed with DMF (5 mL) to give a white solid. The solid was stirred in water
(100 mL) at 60 C
for 2 hours, then at room temperature overnight. The suspension was filtered
and washed with water
(2 X 50 mL) to give 3-(2,6-dimethy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione as a white
solid (3.4 g, 38% yield): HPLC: Waters Symmetry C18, 5ttm, 3.9 x 150 mm, 1
mL/min, 240 nm,
20/80 CH3CN/0.1% H3PO4, 5.37 mm (99.8 %); mp: 270-272 C; 1H NMR (DMSO-d6) 5
2.10-2.22
(m, 1H, CHH), 2.43 (s, 3H, CH3), 2.56-2.72 (m, 5H, CH3, 2CHH), 2.76-2.92 (m,
1H, CHH), 5.24
(dd, J = 6, 11 Hz, 1H, NCH), 7.52 (d, J = 8 Hz, 1H, Ar), 7.64 (dd, J = 2, 8
Hz, 1H, Ar), 7.82 (s, 1H,
Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) 5 20.76, 20.95, 23.34, 30.60, 56.47,
120.05, 125.20,
126.39, 135.96, 136.19, 144.87, 153.99, 160.40, 169.53, 172.62; LCMS: MH =
286; Anal Calcd for
C151115N303 + 2 H20: C, 56.07; H, 5.96; N, 13.08. Found: C, 55.73; H, 5.75; N,
13.01.
5.2 2-BENZYLOXY-N-1342,6-DIOXO-P1PERMIN-3-YL)-2-METHYL-4-0X0-
3,4-DERYDRO-QUINAZOLIN-6-YLI-ACETAMIDE
43

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
= "
N 0
N-=
Step 1: To a stirred mixture of 5-amino-isatoic anhydride (1.0 g, 5.6 mmol)
and
triethyl amine (0.8 mL, 9.0 mmol) in acetronitrile (15 mL), was added
benzyloxyacetyl chloride
(0.87 mL, 5.6 mmol) dropwise at room temperature. The mixture was kept at room
temperature
overnight. To the mixture, was added triethylamine (3.1 mL, 22 mmol), 3-amino-
piperidine-2,6-
dione hydrogen chloride (0.92 g, 5.6 mmol), and acetic acid (3.2 mL, 56 mmol).
The mixture was
heated at 80 C for 8 hours. To the mixture, was added water (75 mL). The
suspension was filtered
and washed with water (75 mL) and ethyl acetate (75 mL) to give a dark solid,
which was purified
with column chromatography (Silica Gel, methanol/methylene chloride 0% to 10%
in 15 min) to
give 2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-piperidin-3-y1)-
benzamide as a white solid
(0.28 g, 12% yield): 'H NMR (DMSO-d6) 8 1.92-2.18 (m, 2H, 2C1-IH), 2.50-2.55
(m, 1H, CHH),
2.72-2.84 (m, 114, CHH), 4.03 (s, 2H, CH2), 4.61 (s, 2H, CH2), 4.68-4.77 (m,
1H, NCH), 6.19 (br,
2H, NH2), 6.68 (d, J = 9 Hz, 1H, Ar), 7.30-7.42 (m, 6H, Ar), 7.62 (d, J = 2
Hz, 1H, Ar), 8.43 (d, J =
8 Hz, 1H, NH), 9.44 (s, 1H, NH), 10.84 (s, 1H, NH); 13C NMR (DMSO-d6) 8 24.09,
30.96, 49.12,
69.37, 72.35, 114.27, 116.23, 121.11, 125.99, 126.13, 127.64, 127.77, 128.27,
137.68, 146.19,
167.28, 168.36, 172.35, 173.01.
Step 2: A solution of 2-amino-5-(2-benzyloxy-acetylamino)-N-(2,6-dioxo-
piperidin-3-y1)-benzamide (0.26 g, 0.6 mmol) and trimethyl orthoformate (2 mL)
and p-toluene
sulfonic acid (60 mg) in acetonotrile (10 mL) was heated to reflux for 21
hours. To the mixture, was
added water (25 mL) and ether (25 mL). The suspension was filtered and washed
with water (50
mL) and ethyl acetate (50 mL) to give 2-benzyloxy-N43-(2,6-dioxo-piperidin-3-
y0-2-methyl-4-
oxo-3,4-dihydro-quinazolin-6-y1Facetamide as a white solid (180 mg, 72%
yield): HPLC: Waters
Symmetry CB, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.87
min
(99.3%); mp: 248-250 C; 1H NMR (DMSO-d6) 8 2.14-2.16(m, 1H, CHIT), 2.62-2.87
(m, 3H, CH2,
CHB), 4.15 (s, 2H, CH2), 4.64 (s, 2H, CH2), 5.49-5.50 (m, 1H, NCH), 7.31-7.41
(m, 5H, Ar), 7.68
(d, J = 9 Hz, 1H, Ar), 8.06-8.10 (m, 1H, NH), 8.28 (s, 1H, CH), 8.55 (br, 1H,
Ar), 10.24 (s, 1H,
NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) 8 23.05, 31.48, 58 (br), 69.87,
72.92, 115.69, 122.15,
127.30, 128.16, 128.28, 128.34, 128.77, 137.98, 138.14, 144.06, 146.48,
160.10, 168.93, 170.43,
172.90; LCMS: MH = 421; Anal Calcd for C22H20N405: C, 62.85; H, 4.79; N,
13.33. Found: C,
60.60; H, 4.29; N, 12.54. '
5.3 3-(6-FLUOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
44

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WO 2009/042177 PCT/US2008/011124
=N=0_04
N 0
To a stirred mixture of 2-amino-5-fluorobenzoic acid (1.2 g, 7.8 mmol) and
imidazole (0.63 g, 9.3 mmol) in acetonitrile (15 mL), was added acetyl
chloride (0.66 mL, 9.3
mmol) at room temperature. The mixture was stirred at room temperature
overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.3 g, 7.7
mmol), imidazole
(1.2 g, 17 mmol) and triphenyl phosphite (2.2 mL, 8.5 mmol) and heated to
reflux for 22 hours. The
suspension was filtered and washed with water (2 X 50 mL), ethyl acetate (2 X
50 mL), and water
(50 mL) to give 3-(6-fluoro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione as a white
solid (1.2 g, 53% yield): HPLC: Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1
mL/min, 240 nm,
20/80 CH3CN/0.1% H3PO4, 5.99 min (99.3 %); mp: 273-275 C; IH NMR (DMSO-d6) 5
2.13-2.23
(m, 1H, CHH), 2.57-2.71 (m, 5H, CH3, 2CHH), 2.75-2.95 (m, 1H, CHH), 5.30 (dd,
J = 6, 11 Hz, 1H,
NCH), 7.70-7.73 (m, 3H, Ar), 11.06 (s, 1H, NH); I3C NMR (DMSO-d6) 8 20.82,
23.31, 30.58,
56.63, 110.54 (d, Jc-F = 23 Hz), 121.40 (d, Jc_F = 8 Hz), 123.24 (d, Jc-F = 24
Hz), 129.47 (d, Jc_F = 8
Hz), 143.75, 154.45, 159.83 (d, Jc..F = 245 Hz), 159.86 (d, Jc-F. = 3 Hz),
169.37, 172.58; LCMS: MH
= 290; Anal Calcd for C14H12N303F + 1.3 H20: C, 53.78; H, 4.71; N, 13.44.
Found: C, 53.75; H,
4.61;N, 13.50.
5.4 3-(6-CHLOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
ci
N 0
To a stirred mixture of 2-amino-5-chlorobenzoic acid (2.0 g, 12 mmol) and
imidazole (1.0 g, 14 mmol) in acetonitrile (30 mL), was added acetyl chloride
(1.0 mL, 14 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (1.9 g, 12 mmol),
imidazole (1.8 g, 26
mmol) and triphenyl phosphite (3.7 mL, 26 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(6-chloro-2-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (2.9 g, 80% yield):
HPLC: Waters Symmetry
C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 6.65 min
(98.5 %); n1P:
276-278 C; IH NMR (DMSO-d6) 8 2.15-2.24 (m, 1H, CHH), 2.58-2.71 (m, 5H, CH3,
2C1-W), 2.78-
2.92 (m, 1H, CHH), 5.30 (dd, J = 6, 11 Hz, 1H, NCH), 7.66 (d, J = 9 Hz, 2H,
Ar), 7.85 (dd, J = 3, 9
Hz, 1H, Ar), 7.98 (d, J = 2 Hz, 1H, Ar), 11.06 (s, 1H, NH); "C NMR (DMSO-d6) 5
20.79, 23.45,
30.57, 56.71, 121.47, 124.89, 128.89, 130.77, 134.87, 145.57, 155.67, 159.53,
169.31, 172.56;

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
LCMS: MH = 306, 308; Anal Calcd for C14H12N303C1+ 2 H20: C, 49.20; 14, 4.72;
N, 12.30; Cl,
10.37. Found: C, 49.34; H, 4.57; N, 12.20; CI, 10.39.
5.5 3-(6-BROM0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
Br
*
N
N= _______________________________
Step 1: A stirred mixture of 5-bromo-isatoic anhydride (6.0 g, 25 mmol), 3-
amino-
piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol), triethylamine (18 mL,
129 mmol), and
acetic acid (15 mL, 262 mmol) in acetonitrile (60 mL) was heated at 90 C for
18 hours. The
suspension was filtered and washed with acetonitrile (2 X 80 mL), water (2 X
80 mL) and ethyl
acetate (2 X 80 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-bromo-
benzamide as a white
solid (5.8 g, 72% yield): LCMS: MH= 326, 328. The sample was used in the next
step without
further purification.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yI)-5-bromo-benzamide
(1.0 g, 3 mmol) and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic
acid (250 mg) in
acetonotrile (10 mL) was heated to reflux for 7 days. The suspension was
filtered and washed with
ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-
bromo-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as an off-white solid (108 mg, 10%
yield): HPLC: Waters
Symmetry C18, 5p,m, 3.9 x 150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4,
5.17 min
(98.7%); mp: 273-275 C; 1H NMR (DMSO-d6) 8 2.14-2.27 (m, 1H, CHH), 2.56-2.69
(m, 2H,
2CHH), 2.64 (s, 3H, CH3), 2.72 -2.90 (m, 1H, CHH), 5.29 (dd, J = 6, 11 Hz, 1H,
NCH), 7.58 (d, J =
9 Hz, 1H, Ar), 7.98 (dd, J 2, 9 Hz, 1H, Ar), 8.12 (d, J = 2 Hz, 1H, Ar), 11.06
(s, 1H, NH); 13C
NMR (DMSO-d6) 8 20.72, 23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95,
137.51, 145.76,
155.74, 159.32, 167.24, 172.49; LCMS: MH = 350, 352; Anal Calcd for
C14H12N303Br: C, 48.02; H,
3.45; N, 12.00. Found: C, 48.02; H, 3.18; N, 11.76.
5.6 3-(6-HYDROXY-2-METHYL-4-0X0-4H-OUINAZOLLN-3-YL)-
PIPERIDINE-2,6-DIONE
0 N 0
0
HO al
N*C
To a stirred mixture of 2-amino-5-hydroxybenzoic acid (5.1 g, 33 mmol) and
imidazole (5.0 g, 73 mmol) in acetonitrile (60 mL), was added acetyl chloride
(5.2 mL, 73 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (6.0 g, 37 mmol),
imidazole (5.0 g, 73
mmol) and triphenyl phosphite (10.5 mL, 40 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (100 mL) and conc HC1 until pH ¨1. The solvent was
removed in vacuo.
46

CA 02704710 2010-03-23
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To the residue, was added water (50 mL). The aqueous layer was extracted with
ethyl acetate (50
mL). To the aqueous layer, was added ethyl acetate (50 mL), and the mixture
was stirred at room
temperature to give a suspension. The suspension was filtered to give a solid,
which was stirred in
methanol (50 mL) overnight. The suspension was filtered and washed with
methanol (2 X 30 mL)
and water to give 3-(6-hydroxy-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-
2,6-dione as an off-
white solid (2.97 g, 31% yield): HPLC: Waters Symmetry C18, 511m, 3.9 x 150
mm, 1 mL/min, 240
nm, 5/95 grad 95/5 in 5 min CH3CN/0.1% H3PO4, 4.50 min (96.8 %); mp: 315 -317
C; 1H NMR
(DMSO-d6) 8 2.13-2.18 (m, 1H, CHH), 2.58 (s, 3H, CH3), 2.62-2.71 (m, 2H,
2CHH), 2.78-2.91 (m,
1H, CHH), 5.22 (dd, J = 6, 11 Hz, 1H, NCH), 7.24-7.32 (m, 211, Ar), 7.49 (d, J
= 9 Hz, 1H, Ar),
10.07 (s, 1H, OH), 11.00 (s, 111, NH); 13C NMR (DMSO-d6) 8 20.97, 23.10,
30.59, 56.36, 108.59,
121.24, 124.13, 128.19, 140.14, 151.39, 155.89, 160.24, 169.58, 172.63; LCMS:
MR = 288; Anal
Calcd for CHHI3N304+ 1 H20: C, 55.08; H, 4.95; N, 13.76. Found: C, 54.82; H,
4.74; N, 13.54.
5.7 3-(6-CHLOR0-4-0X0-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
N
N--=/
Step 1: A stirred mixture of 5-chloroisatoic anhydride (0.51 g, 2.5 mmol), 3-
amino-
piperidine-2,6-dione hydrogen chloride (0.42 g, 2.5 mmol), triethylamine (1.8
mL, 12.7 mmol), and
acetic acid (1.5 mL, 25.3 mmol) in acetonitrile (5 mL) was heated at 150 C in
a microwave oven
for 5 miutes. The suspension was filtered and washed with water (50 mL) and
ethyl acetate (20 mL)
to give 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-chloro-benzamide as a white
solid (0.31 g, 42%
yield): 1H NMR (DMSO-d6) 8 1.91-2.12 (m, 211, 2CHH), 2.50-2.56 (m, 1H, CHH),
2.72-2.80 (m,
1H, CHH), 4.71-4.76 (m, 111, NCH), 6.58 (brs, 214, NH2), 6.74 (d, J = 8 Hz,
1H, Ar), 7.19 (dd, J = 2,
9 Hz, 1H, Ar), 7.58 (t; J = 2 Hz, 1H, Ar), 8.62 (d, J = 8 Hz, 111, NH), 10.86
(s, 1H, NH); 13C NMR
(DMSO-d6) 8 23.99, 30.89, 49.00, 114.62, 117.60, 118.04, 127.25, 131.63,
148.61, 167.37, 172.20,
172.93; LCMS: MH= 282, 284.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-chloro-benzamide
(0.31 g, 1.1 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic
acid (50 mg) was
heated to 150 C in a microwave oven for 10 minutes. The suspension was
filtered and washed with
ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-
chloro-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (230 mg, 74% yield):
HPLC: Waters
Symmetry Cig, 5p.m, 3.9 x 150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4,
4.01 min
(100%); mp: 302-305 C; 11-INMR (DMSO-d6) 8 2.13-2.20 (m, 1H, CHH), 2.62-2.93
(m, 3H, CI-12,
CHB), 5.52 (br, 1H, NCH), 7.76 (d, J = 9 Hz, 1H, Ar), 7.91 (dd, J = 2, 9 Hz,
1H, Ar), 8.10 (d, J = 2
Hz, 1H, Ar), 8.41 (s, 1H, Cl]), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) 8 22.39,
30.87, 56.29 (br),
122.56, 125.05, 129.47, 131.59, 134.82, 146.19, 147.75, 158.73, 169.68,
172.39; LCMS: MH = 292,
294; Anal Calcd for CI3Hi0N303C1: C, 53.53; H, 3.46; N, 14.41. Found: C,
53.43; H, 3.21; N, 14.27.
47

CA 02704710 2010-03-23
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5.8 3-(6-BROM0-4-0X0-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
Br
0 0 H
N=1 _______________________________
Step 1: A stirred mixture of 5-bormo-isatoic anhydride (6.0 g, 25 mmol), 3-
amino-
piperidine-2,6-dione hydrogen chloride (4.1 g, 25 mmol), triethylamine (18 mL,
129 mmol), and
acetic acid (15 mL, 262 mmol) in acetonitrile (60 mL) was heated at 90 C for
18 hours. The
suspension was filtered and washed with acetonitrile (2 X 80 mL), water (2 X
80 mL) and ethyl
acetate (2 X 80 mL) to give 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-bromo-
benzamide as a white
solid (5.8 g, 72% yield): LCMS: MH= 326, 328. The sample was used in the next
step without
further purification.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-bromo-benzamide
(0.51 g, 1.5 mmol) and trimethyl orthoformate (2 mL) and p-toluene sulfonic
acid (150 mg) in
acetonitrile (10 mL) was heated to reflux for 12 hours. To the mixture, was
added water (70 mL),
and stirred at room temperature for 2 hours. The suspension was filtered and
washed with ethyl
acetate (10 mL). The solid in NMP (3 mL) was heated at 80 C. To the solution,
was added water
(1.5 mL), and the mixture was allowed to cool to room temperature. The
suspension was filtered
and washed with NMP (1 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-
4H-quinazolin-
3-y1)-piperidine-2,6-dione as a white solid (350 mg, 68% yield): HPLC: Waters
Symmetry C18,
5t.tm, 3.9 x 150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.18 min
(99.9%); mp: 312-
314 C; IH NMR (DMSO-d6) 8 2.14-2.21 (m, 111, CHH), 2.60-2.74 (m, 211, 2CHH),
2.83-2.93 (m,
111, CHI]), 5.51 (brs, 1H, NCH), 7.68 (d, J = 9 Hz, 1H, Ar), 8.03 (dd, J = 2,
9 Hz, 1H, Ar), 8.24 (d, J
= 2 Hz, 1H, Ar), 8.42 (s, 1H, Cl]), 11.19 (s, 1H, NH); 13C NMR (DMSO-d6) 8
22.45, 30.93, 55.49,
119.83, 122.96, 128.23, 129.65, 137.61, 146.52, 147.94, 158.66, 169.75,
172.46; LCMS: MH = 336,
338; Anal Calcd for C13H10N303Br + 0.3 1420: C, 45.72; H, 3.13; N, 12.30; Br,
23.39. Found: C,
45.46; H, 2.75; N, 12.15; Br, 22.81.
5.9 3-(6-METHYL-4-0X0-4H-QUINTAZOLIN-3-YL)-PEPERIDINE-2,6-DIONE
0 0
0
N--=/
Step 1: A mixture of 2-amino-5-methylbenzoic acid (1.0 g, 6.6 mmol) and CDI
(1.0
g, 6.1 mmol) in acetonitrile (15 mL) was stirred at room temperature for 1.5
hours. To the
suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.0 g,
6.1 mmol) and
sodium hydrogen carbonate (0.45 g, 3.6 mmol), and the mixture was heated at 50
C for 21 hours.
The suspension was cooled to room temperature for 1 hour. The suspension was
filtered and
washed with acetonitrile (20 mL), water (2 X 20 mL) and ethyl acetate (20 mL)
to give 2-amino-N-
48

CA 02704710 2015-03-19
53686-95
(2,6-dioxo-piperidin-3-y1)-5-rnethy1-benzarnide as a blue solid (1.1 g, 63%
yield): NMR
(DMSO-d6) 8 1.91-1.98 (m, 1H, CHH), 2.05-2.14(m, 1H, CHH), 2.17 (s, 3H, CH3),
2.50-2.56 (m,
1H, CH!)), 2.73-2.85 (m, 1H, CH!)), 4.69-4.77 (m, 1H, NCH), 6.20 (br, 2H,
NH2), 6.63 (d, J = 9 Hz,
1H, Ar), 7.00 (dd, J = 2, 8 Hz, 1H, Ar), 7.34 (d, J = 2 Hz, 1H, Ar), 8.43 (d,
J = 8 Hz, 11-1, NB), 10.84
(s, 1H, NH); 13C NMR (DMSO-do) 8 19.89, 24.13, 30.92, 48.93, 113.87, 116.48,
122.81, 127.87,
132.72, 147.40, 168.55, 172.40, 172.97.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-5-methyl-benzamide
(0.45 g, 1.7 mmol) and trirnethyl orthoformate (4 mL) and p-toluene sulfonic
acid (80 mg) was
heated to 160 C in a microwave oven for 8 minutes. To the suspension, was
added methanol (20
TM
mL), methylene chloride (20 mL), and Celite (5 mL). The solvent was removed in
vacuo. The
reside was placed in a SIM and was purified with column chromatography (Silca
Gel,
methanol/methylene chloride 0% gradient 10% in 15 min) to give as 3-(6-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a blue solid (50 mg, 9% yield): HPLC:
Waters Symmetry
C 1 8, 5 m, 3.9 x 150 mm, 1 rnL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.78 min
(96.1%); !TIP:
=
285-287 C; 111 NMR (DMSp-do) 8 2.11-2,18 (m, 1H, CHH), 2.46 (s, 3H, CH3),
2.56-2.74 (m, 2H,
2CHH), 2.82-2.93 (m, 1H, CHH), 5.48 (br, 1H, NCH), 7.61 (d, J = 8 Hz, 1H, Ar),
7.70 (dd, J = 2, 8
Hz 1H, Ar), 7.94 (br, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s,111, NH); "C NMR
(DMSO-do) 620.72,
22.51, 30.91, 57.00 (br), 121.09, 125.38, 127.00, 135.89, 137.07, 145.46,
146.45, 159.60, 169.88,
172.44; LCMS: MB = 272; Anal Calcd for C141-113N303: C, 61.99; 11,4.83; N,
15.49. Found: C,
61.78; H, 4.57; N, 15.34.
=
5.10 3-(6-AMINO-2-111:ETHYL-4-70X0-411-OUINAZOLIN-3-YL)-PIPERIDINE- =
2 6-DIONE
o 0 N 0
H214
Stepl : To a stirred mixture of 2-amino-5-nitrobenzoic acid (5.0 g, 28 mmol)
and
imidazole (2.2 g, 33 mmol). in acetonitrile (50 mL), was added acetyl chloride
(2.3 mL, 33 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol),
imidazole (4.1 g, 60
mmol) and triphenyl phosphite (8.7 mL, 33 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(2-methyl-6-nitro-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as an off- white solid (5.3 g, 61%
yield): IH NMR (DMS0-
do) 62.19-2.26 (m, I H, CHH), 2.60-2.69 (m, 2H, 2CHH), 2.72 (s, 311, CH3),
2.79-2.87 (m, 1H,
Cl-!!)), 5.37 (dd, J = 5, 11 Hz, 1H, NCH), 7.83 (d, J = 9 Hz, 1H, Ar), 8.56
(dd, J = 3, 9 Hz, 111, Ar),
8.74 (dt, J = 3 Hz 1H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) 620.69,
23.82, 30.57, 56.98,
119.46, 120.20, 122.21, 128.45, 128.74, 144.90, 150.85, 159.13, 159.78,
169.12, 172.53.
49

CA 02704710 2010-03-23
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Step 2: A suspension of 3-(2-methy1-6-nitro-4-oxo-4H-quinazolin-3-y1)-
piperidine-
2,6-dione (4.1 g, 13 mmol) and 20% Pd(OH)2/C (0.9 g) in cyclohexene (20 mL)
and DMF (60 mL)
was heated in a 125 C oil bath overnight. The suspension was filtered thru a
pad of Celite, and
washed with DMF (30 mL). The DMF solution and Charcoal (4 g) were stirred at
room temperature
for 5 hours. The suspension was filtered thru a pad of Celite. The solvent was
removed in vacuo.
To the residue, was added DMF (20 mL), and then water (80 mL) to give a
suspension. The
suspension was filtered and washed with water (50 mL), ethyl acetate (50 mL)
and water (50 mL) to
give a brown solid, which was purified with preparative HPLC (C18 5/95 for 2
minutes then
gradient to 50/50 in 18 min CH3CN/H20) to give 3-(6-amino-2-methy1-4-oxo-4H-
quinazolin-3-y1)-
piperidine-2,6-dione as a white solid (1.15 g, 31% yield): HPLC: Waters Xterra
C18, 5 m, 3.9 x 150
mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% NH4HCO2, 5.31 min (99.8 %); mp: 314-316
C; 114
NMR (DMSO-d6) 8 2.08-2.14 (m, 111, CHH), 2.54 (s, 3H, CH3), 2.55-2.67 (m, 2H,
2CHH), 2.75-
2.90 (m, 111, CHH), 5.16 (dd, J = 5, 11 Hz, 1H, NCH), 5.59 (brs, 2H, NH2),
7.04-7.08 (m, 2H, Ar),
7.31-7.34 (m, 1H, Ar), 10.97 (s, 1H, NH); 13C NMR (DMSO-d6) 8 21.06, 22.96,
30.62, 56.22,
105.89, 121.34, 122.61, 127.35, 137.89, 147.63, 149.24, 160.39, 169.68,
172.66; LCMS: MH = 287;
Anal Calcd for C14Hi4N403+ 1 H20: C, 55.26; H, 5.30; N, 18.41. Found: C,
54.99; H, 5.22; N,
18.35.
5.11 [3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-DIHYDRO-
QUINIAZOLIN-6-YLMETHYL1-CARBAMIC ACID TERT-BUTYL ESTER
*
N=cN 0
Step 1: A mixture of 5-methyl-2-nitro-benzoic acid methyl ester (93.95 g,
481.35
mmol), 1,3-dibromo-5,5-dimethylhydantoin (75.70 g, 264.74 mmol), in methyl
acetate (550 mL)
was heated at 78 C for 40 minutes while stirred with a mechanical stirrer.
Then a solution of 2,2'-
azobisisobutyro-nitrile (3.95 g, 24.07 mmol) in methyl acetate (80 mL) was
added, and the mixture
was heated at about 75 C for 13 hours. The mixture was allowed to cooled to
15 C and stirred for
2 hours to age the precipitate. The suspension was filtered, washed with 10 C
methyl acetate (2 x
50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL).
The organic layer was
washed with 2% brine (2 x 500 mL) and water (2 x 500 mL), and concentrated to
about 2 volumes.
To the mixture, was added t-butyl methyl ether (or MTBE, 300 mL). The mixture
was heated at
about 70 C for 15 minutes, cooled to about 53 C over one hour, seeded with
the product (about 250
mg, or simply re-crystallized) at 45 C, then at 20-25 C, while blowing
nitrogen with a glass pipette
overnight. The resulting solid was filtered via a medium pore-sized funnel,
washed with a pre-
cooled 10 C mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in
hood overnight to
give 5-bromomethy1-2-nitro-benzoic acid methyl ester as an off-white solid
(58.3 g, 44.0% yield).
The solid was used in the next step without further purification.

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
Step 2: A stirred mixture of 5-bromomethy1-2-nitro-benzoic acid methyl ester
(50.5
g, 184 mmol), di-tert-butyl iminodicarboxylate (40.15 g, 185 mmol), cesium
carbonate (123.1 g,
377.7 mmol), and lithium iodide (1.23 g, 9.21 mmol) in 2-butanone (556 mL) was
heated to reflux
in a 100 C oil bath for 12 hours while stirred with a mechanical stirrer. The
mixture was allowed to
cool to room temperature. To the mixture, was added brine (300 mL), water (300
mL), and ethyl
acetate (750 mL), and the mixture was stirred for 10 minutes. The suspension
was filtered through a
pad of Celite. The two layers were separated, and the organic layer was
evaporated to a less
volume. The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The
combined organic
layers were washed with brine (500 mL), dried over magnesium sulfate while de-
colored at the same
time by charcoal at room temp with stirring for 30 minutes. The black mixture
was filtered through
a pad of Celite. The filtrate was evaporated to give 5-(di-tert-
butoxycarbonylamino-methyl)-2-nitro-
benzoic acid methyl ester as a brown oil (74.18 g, 98% yield). The product was
used in the next
step without further purification.
Step 3: To a stirred brown solution of 5-(di-tert-butoxycarbonylamino-methyl)-
2-
nitro-benzoic acid methyl ester (74.18 g, 180.7 mmol) in methylene chloride
(700 mL) was added
trifluoroacetic acid (26.2 mL, 352.4 mmol), and the mixture was stirred at
room temp overnight.
Sat. sodium bicarbonate (400 mL) was added to the solution, and the mixture
was stirred for 10
minutes. The organic layer was separated, dried over magnesium sulfate, and
evaporated to give 5-
(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown
oil (52.5 g, 94%
crude yield). The product was used in the next step without further
purification.
Step 4: A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid
methyl ester (52.5 g, 169.3 mmol), lithium hydroxide (4.86 g, 203.1 mmol) in
methanol (546 mL)
and water (273 mL) was stirred with a mechanical stirrer at room temp
overnight. The methanol
was evaporated, and to the aqueous solution, was added 1 N HC1 (270 mL) to
form the precipitate.
Ether (350 mL) was added, and the mixture was stirred at 0 C for 2 hours. The
mixture was
evaporated. To the residue, was added water (500 mL). The aqueous layer was
extracted with
methylene chloride (3 x 100 mL). The combined organic layers were separated,
dried over
magnesium sulfate, and concentrated to give 5-(tert-butoxycarbonylamino-
methyl)-2-nitro-benzoic
acid as a brown oil (21.0 g, 41% yield). The product was used in the next step
without further
purification.
Step 5: A mixture of 5-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid
(21.0g, 70.9 mmol) in methanol (210 mL) and palladium/carbon (2 g) was
hydrogenated with a Parr-
shaker overnight at 51 psi. The black mixture was filtered through a pad of
Celite, and the filtrate
was evaporated to give a brown oil, which was stirred in ether (300 mL)
overnight. The ether slurry
was filtered to give 2-amino-5-(tert-butoxycarbonylamino-methyl)-benzoic acid
as a brown solid
(9.3 g, 49% yield). The product was used in the next step without further
purification.
Step 6: To a stirred solution of 2-amino-5-(tert-butoxycarbonylamino-methyl)-
benzoic acid (9.3 g, 34.9 mmol), imidazole (2.85 g, 41.9 mmol) in acetonitrile
(120 mL), was added
acetyl chloride (3.0 mL, 41.9 mmol) and stirred at room temp overnight. Then
to the mixture, was
51

CA 02704710 2010-03-23
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added 3-amino-piperidine-2,6-dione hydrogen chloride (5.74 g, 34.9 mmol),
imidazole (4.76 g, 69.8
mmol) and triphenyl phosphite (11.0 mL, 41.9 mmol), and the mixture was heated
to reflux for 6
hours. The mixture was allowed to cool to room temperature, and water (about
400 mL) was added.
The suspension was filtered, washed with water (50 mL), ethyl acetate (20 mL),
ether (50 mL), and
suction dried to give [3-(2,6-dioxo-piperidin-3-y1)-2-methyl-4-oxo-3,4-dihydro-
quinazolin-6-
ylmethyl]-carbamic acid tert-butyl ester as an off-white solid (9.7 g, 70%
yield): HPLC, Waters
Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4,
grad. to 95/5 in
min, kept 5 min, 5.95 min (96.7%); mp, 212.5-214.5 C; IHNMR (DMSO-d6) & 1.40
(s, 9H,
CMe3), 2.15-2.18 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.23 (d, J = 6
Hz, 2H, CH2NH),
5.26 (dd, J = 6, 11 Hz, 1H, Cl]), 7.52 (t, J = 6 Hz, 1H, CH2NH), 7.56-7.88 (m,
3H, Ar), 11.03 (s, 1H,
NH); I3C NMR (DMSO-d6) 8 20.92, 23.40, 28.20, 30.62, 42.97, 56.52, 77.94,
119.98, 123.50,
126.51, 133.74, 138.76, 145.75, 154.52, 155.79, 160.44, 169.47, 172.61. LCMS
MH = 401; Anal
Calcd For C20H241\1405: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.83; H, 5.98;
N, 13.85.
5.12 3-(6-AMINOMETHYL-2-METHYL-4-0X0-4H-OUINAZOLINT-3-YL)-
PIPERMINE-2,6-DIONEHYDROGEN CHLORIDE
I-12N
H-Cl
\1W N 0
N=c
Step 1: To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-y1)-2-methy1-
4-
oxo-3,4-dihydro-quinazolin-6-ylmethylj-carbamic acid tert-butyl ester (3.5 g,
8.7 mmol) in
methanol (36 mL) and methylene chloride (36 mL), was added 2 M HC1 in ether
(102 mL), and the
mixture was stirred overnight. The solvent was evaporated, and the residue was
stirred in ether (100
mL) for 2 hours. The suspension was filtered to give 3-(6-aminomethy1-2-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione hydrogen chloride as a light yellow
solid (3.2 g, 109% crude
yield). The product was used in the next step without further purification.
Step 2: 3-(6-Aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione hydrogen chloride (0.95 g) was dissolved in water (100 mL). The solution
was washed with
ethyl acetate (2 x 100 mL). The aqueous layer was evaporated to give 3-(6-
aminomethy1-2-methy1-
4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione hydrogen chloride as an off-
white solid (0.79 g,
84% yield); HPLC, Waters Xterra RP 18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm,
Waters LC
Module 1, 05/95 CH3CN/0.1% (HCO2)NH4 is Crat, 4.67 min (98.5%); mp, 299-301
C; IHNMR
(DMSO-d6) & 2.18-2.24 (m, 1H, CHH), 2.59-2.89 (m, 6H, CHCH2, CH3), 4.14-4.19
(m, 2H, ArCH2),
5.34 (dd, J = 5, 11 Hz, 1H, Cl]), 7.71-8.20 (m, 3H, Ar), 8.54 (brs, 3H, CINI-
13), 11.08 (s, 1H, NH);
I3C NMR (DMSO-d6) 620.86, 22.97, 30.60, 41.61, 56.75, 119.85, 125.75, 126.83,
132.81, 135.80,
145.35, 156.51, 159.96, 169.23, 172.59. LCMS MH = 301; Anal Calcd For
C15H17N403C1 + 1.0
H20 and + 0.8 HC1: C, 46.92; H, 5.20; N, 14.59; Cl, 16.62. Found: C, 46.72; H,
5.15; N, 14.29; Cl,
16.59.
52

CA 02704710 2010-03-23
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5.13 HEPTANOIC ACID [3-(2,6-DIOXO-PIPERMIN-3-YL)-2-METHYL-4-0X0-
34-DIHYDRO-OUINAZOLIN-6-YLMETHYLI-AMIDE
0 0 0
N=
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10
mL), was added
heptanoyl chloride (0.34 mL, 2.2 mmol) and N, N-diisopropyl ethylamine (0.60
mL, 3.7 mmol).
The mixture was stirred at room temp for one hour. The solvent was evaporated,
and the residue
was purified by flash column chromatography (Silica gel, methanol/methylene
chloride 4%/96%) to
give heptanoic acid [3-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-
quinazolin-6-
ylmethy1]-amide as an off-white solid (349 mg, 58% yield); HPLC, Waters
Symmetry C18, 51.1m, 3.9
x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min,
kept for 5 min,
6.12 min (96.3%); mp, 223-225 C; IHNMR (DMSO-d6) 5 0.84 (t, J = 6 Hz, 3H, CH3
of long chain),
1.24-2.20 (m, 11H, CH2CH2CH2CH2CH2, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.36
(d, J = 6
Hz, 2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, Cl]), 7.56-7.88 (m, 311, Ar), 8.41
(t, J = 6 Hz, 111,
CH2NH), 11.03 (s, 1H, NH); I3C NMR (DMSO-d6) 5 13.86, 20.92, 21.95, 23.39,
25.23, 28.31,
30.61, 30.99, 35.33, 41.57, 56.51, 119.99, 123.79, 126.51, 133.96, 138.38,
145.74, 154.53, 160.40,
169.47, 172.25, 172.60. LCMS MH = 413; Anal Calcd For C22H28N404: C, 64.06; H,
6.84; N, 13.58.
Found: C, 63.76; H, 6.68; N, 13.42.
5.14 CYCLOPROPANECARBOXYLIC ACID [3-(2.6-DIOXO-PIPERIDIN-3-YL)-
2-METHYL-4-0X0-3,4-DIHYDRO-OIJINAZOLIN-6-YLMETHYL1-AMIDE
>¨µ 0 0\
0 IF
N=c _____________________________________
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10
mL), was added
cyclopropanecarbonyl chloride (0.21 mL, 2.3 mmol) and N, N-diisopropyl
ethylamine (0.62 mL, 3.8
mmol). The mixture was stirred at room temperature for one hour. The solvent
was evaporated, and
the residue was purified by flash column chromatography (Silica gel,
methanol/methylene chloride
4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-y1)-2-
methyl-4-oxo-3,4-
dihydro-quinazolin-6-ylmethylkamide as an off-white solid (233 mg, 42% yield);
HPLC, Waters
Symmetry C18, 511m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4,
gradient to 95/5
in 5 min, kept for 5 min, 5.01 min (98.4%); mp, 281-283 C; IHNMR (DMSO-d6) 5
0.64-0.74 (m,
4H, CH2CH2 of cyclopropane ring), 1.57-1.66 (m, 1H, CH of cyclopropane ring),
2.15-2.21 (m, 1H,
Cl]), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.39 (d, J = 5 Hz, 2H, CH2NH), 5.26 (dd,
J = 6, 11 Hz, 111,
53

CA 02704710 2010-03-23
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Cl]), 7.57-7.89 (m, 3H, Ar), 8.68 (t, J = 6 Hz, 1H, CH2N1]), 11.03 (s, 1H,
NH); I3C NMR (DMSO-
d6) 8 6.31, 13.55, 20.93, 23.40, 30.61, 41.77, 56.53, 120.01, 123.78, 126.58,
134.02, 138.34, 145.78,
154.55, 160.44, 169.47, 172.62, 172.70. LCMS MH = 413; Anal Calcd For
C19H20N404: C, 61.95;
H, 5.47; N, 15.21. Found: C, 61.86; H, 5.49; N, 15.04.
5.15 3-f3-(2,6-DIOXO-PIPERIDINT-3-YL)-2-METHYL4-0X0-3,4-D1HYDRO-
QUINAZOLINT-6-YLMETHYL1-1,1-DIMETHYL-UREA
N
/ 0 V
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) in acetonitrile (10
mL), was added
dimethyl carbamyl chloride (0.21 mL, 2.2 mmol) and N, N-diisopropyl ethylamine
(0.62 mL, 3.8
mmol). The mixture was stirred at room temperature overnight. The solvent was
evaporated, and
the residue was purified by flash column chromatography (Silica gel,
methanol/methylene chloride
4%/96%) to give 343-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-
quinazolin-6-
ylmethy1]-1,1-dimethyl-urea as an off-white solid (290 mg, 52% yield); HPLC,
Waters Symmetry
C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to
95/5 in 5 min,
kept for 5 min, 4.66 min (98.7%); mp, 264-268 C; IHNMR (DMSO-d6) 8 2.14-2.20
(m, 1H, Cl]),
2.56-2.86 (m, 12H, N(CH3)2, CHCH2, CH3), 4.31 (d, J = 5 Hz, 211, CH2NH), 5.26
(dd, J = 6, 11 Hz,
1H, Cl]), 7.00 (t, J = 5 Hz, 1H, CH2N1]), 7.54-7.89 (m, 3H, Ar), 11.03 (s, 1H,
NH); I3C NMR
(DMSO-d6) 8 20.95, 23.38, 30.61, 35.85, 43.20, 56.49, 119.88, 123.54, 126.30,
133.91, 139.98,
145.59, 154.27, 158.09, 160.50, 169.49, 172.62. LCMS MR = 372; Anal Calcd For
C18H21N504+
0.5 H20: C, 56.83; H, 5.83; N, 18.41. Found: C, 56.71; H, 5.81; N, 18.18.
5.16 2-(4-CHLORO-PHENYL)-N-13-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-
4-0X0-3,4-DIHYDRO-OUINAZOLIN-6-YLMETHYLI-ACETAMIDE
Aik N
0 0
CI
0
N=1
To a stirred solution of (4-chloro-pheny1)-acetic acid (0.30 g, 1.8 mmol) in
DMF (8
mL) in a 40 C oil bath, was added 1.1' carbonyldiimidazole (0.31 g, 1.9 mmol),
and the mixture
was stirred for one hour. Then 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-
y1)-piperidine-
2,6-dione hydrogen chloride (0.59 g, 1.7 mmol) was added, and the mixture was
stirred for 15
minutes. The solvent was evaporated, and the residue was purified by flash
column chromatography
(Silica gel, methanol/methylene chloride 4%/96%) to give 2-(4-chloro-pheny1)-N-
[3-(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide as
a white solid (550
mg, 70% yield); HPLC, Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240
nm, 10/90
54

CA 02704710 2010-03-23
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CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.00 min (98.7%); mp,
229.5-231.5 C;
1HNMR (DMSO-d6) 5 2.15-2.21 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 3.50
(s, 211,
ArCH2), 4.37 (d, J = 5 Hz, 2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, Cl]), 7.27-
7.90 (m, 7H, Ar),
8.67 (t, J = 5 Hz, 1H, CH2NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) 5 20.92,
23.40, 30.63,
41.39, 41.87, 56.53, 120.02, 123.99, 126.57, 128.13, 130.87, 131.09, 134.03,
135.21, 137.97,
145.81, 154.61, 160.38, 169.47, 169.85, 172.61. LCMS MH = 453, 455; Anal Calcd
For
C231121N404C1: C, 61.00; 11,4.67; N, 12.37; Cl, 7.83. Found: C, 60.88; H,
4.60; N, 12.27; Cl, 7.89.
5.17 1-[3-(2,6-DIOXO-PIPERMIN-3-YL)-2-METHYL-4-0X0-3,4-DIHYDR0-
OUINAZOLIN-6-YLMETHYL1-3-HEXYL-UREA
N4oN
*
N 0
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine
(0.29 mL, 2.1 mmol)
in THF (12 mL) at 5-10 C, was added hexyl isocyanate (0.25 g, 1.9 mmol), and
the mixture was
stirred at room temperature overnight. The mixture was quenched with methanol
(-1 mL), and the
solvent was evaporated. The residue was purified by flash column
chromatography (Silica gel,
methanol/methylene chloride 4%/96%) to give 143-(2,6-dioxo-piperidin-3-y1)-2-
methy1-4-oxo-3,4-
dihydro-quinazolin-6-ylmethy11-3-hexyl-urea as an off-white solid (410 mg, 65%
yield); HPLC,
Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%
H3PO4, grad. to
95/5 in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222 C;1HNMR (DMSO-d6) 5
0.85 (t, J = 6
Hz, 3H, CH3CH2CH2), 1.24-1.38 (m, 811, CH2CH2CH2CH2), 2.15-2.20 (m, 1H, CHH),
2.56-3.03 (m,
611, CHCH2, CH3), 4.30 (d, J = 6 Hz, 2H, ArCH2NH), 5.26 (dd, J = 6, 11 Hz, 1H,
Cl]), 5.97 (t, J = 5
Hz, 111, CH2NH), 6.40 (t, J = 6 Hz, 111, ArCH2NH), 7.55-7.89 (m, 3H, Ar),
11.02 (s, 1H, NH); 13C
NMR (DMSO-d6) 5 13.88, 20.93, 22.05, 23.38, 26.03, 29.94, 30.63, 31.02, 39.35,
42.44, 56.51,
119.96, 123.46, 126.40, 133.81, 139.87, 145.64, 154.36, 157.99, 160.46,
169.47, 172.60. LCMS MH
= 428; Anal Calcd For C22H29N504: C, 61.81; H, 6.84; N, 16.38. Found: C,
61.50; H, 6.82; N, 16.23.
5.18 1-(4-CHLORO-PHENYL)-3-f3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-
4-0X0-34-DIHYDRO-OUINAZOLIN-6-YLMETHYL1-UREA
N-4
N
0 0
N=1
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine
(0.27 mL, 2.0 mmol)
in THF (8 mL) at 5-10 C, was added 4-chlorophenyl isocyanate (0.28 g, 1.8
mmol), and the

CA 02704710 2010-03-23
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mixture was stirred at room temperature overnight. The mixture was quenched
with methanol (-1
mL), and the solvent was evaporated. The residue was purified by flash column
chromatography
(Silica gel, methanoUmethylene chloride 4%/96%) to give 1-(4-chloro-pheny1)-
343-(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyll-urea as an
off-white solid (400
mg, 63% yield); HPLC, Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240
nm, 10/90
CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.18 min (98.9%); mp,
225-227 C;
1HNMR (DMSO-d6) 5 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.41
(d, J = 5 Hz,
2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, CH), 6.81 (t, J = 6 Hz, 1H, CH2NH),
7.23-7.95 (m, 7H,
Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) 5 20.93, 23.38,
30.61, 42.33, 56.54,
119.23, 120.01, 123.67, 124.57, 126.53, 128.42, 133.95, 139.05, 139.37,
145.74, 154.53, 155.09,
160.46, 169.47, 172.60. LCMS MH = 454, 456; Anal Calcd For C22H20N504C1+ 0.8
H20: C, 56.43;
H, 4.65; N, 14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
5.19 1-13-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-D1HYDRO-
QUINAZOLIN-6-YLMETHYL1-3-M-TOLYL-UREA
N-4
N
= 0_0t_Ni
0
1-(1
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine
(0.29 mL, 2.1 mmol)
in THF (12 mL) at 5-10 C, was added m-toluyl isocyanate (0.25 mL, 1.9 mmol),
and the mixture
was stirred at room temperature overnight. The mixture was quenched with
methanol (-1 mL), and
the solvent was evaporated. The residue was purified by flash column
chromatography (Silica gel,
methanoUmethylene chloride 4%/96%) to give 143-(2,6-dioxo-piperidin-3-y1)-2-
methy1-4-oxo-3,4-
dihydro-quinazolin-6-ylmethy1]-3-m-tolyl-urea as an off-white solid (437 mg,
68% yield); HPLC,
Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%
H3PO4, grad. to
95/5 in 5 min, kept 5 min, 5.95 min (99.0%); mp, 200-202 C; IHNMR (DMSO-d6)45
2.07-2.24 (m,
4H, ArCH3, CHH), 2.56-2.88 (m, 611, CHCH2, CH3), 4.40 (d, J = 5 Hz, 2H,
CH2NH), 5.26 (dd, J =
6, 11 Hz, 1H, CH), 6.70-7.95 (m, 8H, Ar and CH2NH), 8.54 (s, 1H, NH), 11.01
(s, 1H, NH); 13C
NMR (DMSO-d6) 8 20.92, 21.19, 23.39, 30.61, 42.30, 56.53, 114.93, 118.27,
120.00, 121.87,
123.63, 126.53, 128.44, 133.94, 137.70, 139.23, 140.26, 145.73, 154.50,
155.22, 160.46, 169.48,
172.61. LCMS MH = 434; Anal Calcd For C23H23N504 + 1.4 H20: C, 60.23; H, 5.67;
N, 15.27.
Found: C, 60.18; H, 5.44;N, 15.09.
5.20 143-(2,6-DIOXO-PIPERMIN-3-YL)-2-METHYL-4-0X0-3,4-DIHYDRO-
QUINAZOLIN-6-YLMETHYLI-3-(4-TRIFLUOROMETHOXY-PHENYL)-
UREA
56

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WO 2009/042177 PCT/US2008/011124
N
.
N=c
To a stirred suspension of 3-(6-aminomethy1-2-methyl-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) and triethylamine
(0.28 mL, 2.1 mmol)
in THF (12 mL) at 5-10 C, was added trifluoromethoxy-phenyl isocyanate (0.29
mL, 1.9 mmol),
and the mixture was stirred at room temperature overnight. The mixture was
quenched with
methanol (-1 mL), and the solvent was evaporated. The residue was purified by
flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 143-
(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy1]-3-(4-
trifluoromethoxy-pheny1)-
urea as an off-white solid (490 mg, 67% yield); HPLC, Waters Symmetry C18,
5pun, 3.9 x 150 mm,
1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min,
6.47 min
(98.6%); mp, 201-203 C; iHNMR (DMSO-d6)45 2.15-2.20 (m, 111, CHH), 2.56-2.90
(m, 6H,
CHCH2, CH3), 4.42 (d, J = 5 Hz, 2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, CH),
6.84 (t, J = 6 Hz,
1H, CH2NH), 7.21-7.96 (m, 7H, Ar), 8.88 (s, 1H, NH), 11.02 (s, 1H, NH); 13C
NMR (DMSO-d6) 8
20.93, 23.39, 30.61, 42.33, 56.53, 118.81, 120.01, 120.17 (q, .1c-F = 255 Hz),
121.54, 123.66, 126.54,
133.93, 139.04, 139.69, 142.08, 145.76, 154.52, 155.12, 160.46, 169.48,
172.60. LCMS MH = 504;
Anal Calcd For C23H20N505F3 + 0.2 H20: C, 54.48; H, 4.06; N, 13.81; F, 11.24.
Found: C, 54.25; H,
4.00;N, 13.59; F, 11.24.
5.21 N-13-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-DIHYDRO-
QUINAZOLIN-6-YLMETHYL1-4-TRIFLIJOROMETHYLSULFANYL-
BENZAM1DE
F S 0 0
0 *
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) in acetonitrile (10
mL), was added 4-
trifluoromethylthio-benzoyl chloride (0.35 mL, 2.1 mmol) and N, N-diisopropyl
ethylamine (0.58
mL, 3.5 mmol). The mixture was stirred at room temperature for one hour. The
solvent was
evaporated, and the residue was purified by flash column chromatography
(Silica gel,
methanol/methylene chloride 4%/96%) to give N43-(2,6-dioxo-piperidin-3-y1)-2-
methyl-4-oxo-3,4-
dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-sulfanyl-benzamide as an off-
white solid (470
mg, 66% yield); HPLC, Waters Symmetry C18, 51.tm, 3.9 x 150 mm, 1 mL/min, 240
nm, 10/90
CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 6.63 min (96.8%);
mp, 169-171 C;
IHNMR (DMSO-d6)45 2.15-2.20 (m, 1H, CHH), 2.56-2.86 (m, 6H, CHCH2, CH3), 4.60
(d, J = 5 Hz,
2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, CH), 7.59-8.03 (m, 7H, Ar), 9.35 (t, J
= 5 Hz, 1H,
CH2NH), 11.02 (s, 1H, NH); '3C NMR (DMSO-d6) 620.89, 23.41, 30.60, 42.38,
56.52, 120.01,
57

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
123.90, 126.33, 126.64, 128.64, 129.46 (q, Jc_F = 307 Hz), 134.09, 135.91,
136.69, 137.86, 145.85,
154.64, 160.41, 165.28, 169.47, 172.62. LCMS MH = 505; Anal Calcd For
C23H19N404F3S + 0.8
H20: C, 53.24; H, 4.00; N, 10.80; F, 10.98; S, 6.18. Found: C, 53.17; H, 3.83;
N, 10.60; F, 10.74; S,
6.14.
5.22 1-(3-CHLOR0-4-METHYL-PHENYL)-3-1342,6-DIOX0-PIPERIDIN-3-YL)-
2-METHYL-4-0X0-3,4-DIHYDRO-QUINAZOLIN-6-YLMETHYL1-UREA
N4N
* o 0
N=
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.46 g, 1.4 mmol) and triethylamine
(0.27 mL, 1.9 mmol)
in TI-IF (10 mL) at 5-10 C, was added 3-chloro-4-methyl-phenyl isocyanate
(0.24 mL, 1.8 mmol),
and the mixture was stirred at room temperature overnight. The mixture was
quenched with
methanol (-1 mL), and the solvent was evaporated. The residue was purified by
flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-
chloro-4-methyl-
pheny1)-343-(2,6-dioxo-piperidin-3-y0-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-
ylmethyli-urea as
an off-white solid (450 mg, 70% yield); HPLC, Waters Symmetry C18, 5 m, 3.9 x
150 mm, 1
mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min,
6.38 min (98.4%);
mp, 186-188 C; IHNMR (DMSO-d6) sE! 2.15-2.23 (m, 4H, CHH and CH3Ar), 2.56-
2.86 (m, 6H,
CHCH2, CH3), 4.40 (d, J = 6 Hz, 2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, CH),
6.81 (t, J = 5 Hz,
1H, CH2NH), 7.11-7.95 (m, 6H, Ar), 8.75 (s, 1H, NH), 11.02 (s, 1H, NH); I3C
NMR (DMSO-d6) 8
18.71, 20.93, 23.39, 30.61, 42.34, 56.53, 116.45, 117.66, 120.01, 123.67,
126.54, 127.39, 130.99,
132.96, 133.95, 139.05, 139.58, 145.76, 154.51, 155.08, 160.47, 169.47,
172.60. LCMS MH = 468,
470; Anal Calcd For C23H22N504C1+ 0.6 1420: C, 57.71; H, 4.88; N, 14.63; CI,
7.41. Found: C,
57.63; H, 4.96; N, 14.50; Cl, 7.64.
5.23 4-CHLORO-N-[342,6-DIOXO-PIPERIDIN-3-YL)-2-METITYL-4-0X0-3,4-
DIHYDRO-QUINAZOLIN-6-YLMETHYLI-BENZAMIDE
* N
0 * 0 0
N=
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.54 g, 1.6 mmol) in acetonitrile (10
mL), was added 4-
dichloro-benzoyl chloride (0.31 mL, 2.4 mmol) and N, N-diisopropyl ethylamine
(0.66 mL, 4.0
mmol). The mixture was stirred at room temperature for 30 minutes. The solvent
was evaporated,
and the residue was purified by flash column chromatography (Silica gel,
methanol/methylene
chloride 4%/96%) to give 4-chloro-N-[3-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-
oxo-3,4-dihydro-
58

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
quinazolin-6-ylmethyli-benzamide as a white solid (298 mg, 42% yield); HPLC,
Waters Symmetry
C18, 5p,m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to
95/5 in 5 min,
kept for 5 min, 6.00 min (99.0%); mp, 267-269 C; IHNMR (DMSO-d6) 8 2.15-2.18
(m, 1H, CHH),
2.57-2.85 (m, 6H, CHCH2, CH3), 4.59 (d, J = 5 Hz, 2H, CH2NH), 5.26 (dd, J = 6,
11 Hz, 1H, CH),
7.54-7.95 (m, 7H, Ar), 9.24 (t, J = 5 Hz, 1H, CH2NH), 11.02 (s, 111, NH); I3C
NMR (DMSO-d6) 8
20.91, 23.40, 30.60, 42.33, 56.52, 120.01, 123.89, 126.62, 128.44, 129.15,
132.84, 134.09, 136.16,
138.02, 145.83, 154.60, 160.43, 165.23, 169.45, 172.60. LCMS MH = 439, 441;
Anal Calcd For
C22H191\1404C1+ 0.3 1120: C, 59.48; H, 4.45; N, 12.61; Cl, 7.98. Found: C,
59.32; H, 4.10; N, 12.50;
Cl, 7.99.
5.24 N-1342,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-MHYDRO-
QUINAZOLIN-6-YLMETHYL1-3-TRIF'LUOROMETHYL-BENZAMIDE
. 0
N
F
F 0 0
N=1 0
To a stirred solution of 3-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in
DMF
(8 mL) in a 40 C oil bath, was added 1.1' carbonyldiimidazole (0.28 g, 1.7
mmol), and the mixture
was stirred for one hour. Then 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-
y1)-piperidine-
2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) was added, and the mixture was
stirred for 15
minutes. The solvent was evaporated, and the residue was purified by flash
column chromatography
(Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-
piperidin-3-y1)-2-
methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide as
an off-white
solid (430 mg, 59% yield); HPLC, Waters Symmetry C18, 5tun, 3.9 x 150 mm, 1
mL/min, 240 nm,
10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.20 min (98.5%);
mp, 220-222 C;
1HNMR (DMSO-d6) 8. 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.62
(d, J = 5 Hz,
2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 1H, CH), 7.59-8.25 (m, 711, Ar), 9.42 (t,
J = 5 Hz, 1H,
CH2NH), 11.02 (s, 111, NH); 13C NMR (DMSO-d6) 620.90, 23.41, 30.60, 42.45,
56.53, 120.02,
123.79 (q, Jc-F = 11 Hz), 123.79 (d, Jc-F = 3 Hz), 123.95 (q, Jc_F = 275 Hz),
124.04, 126.67, 127.96
(d, Jc-F = 3 Hz), 129.19 (d, Jc-F = 32 Hz), 129.74, 131.38, 134.18, 134.88,
137.81, 145.88, 154.65,
160.43, 164.73, 169.45, 172.59. LCMS MH = 473; Anal Calcd For C23H19N404F3 +
0.3 1120: C,
57.81; H, 4.13;N, 11.73; F,,11.93. Found: C, 57.77; H, 4.11; N, 11.69; F,
11.97.
5.25 N-13-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-DII-IYDRO-
QUINAZOLIN-6-YLMETHYL1-4-TRIFLUOROMETHOXY-BENZAMIDE
0 41 N
F
F-X 0
F N 0
N=-
59

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.49 g, 1.4 mmol) in acetonitrile (10
mL), was added 4-
trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) and N, N-diisopropyl
ethylamine (0.63 mL,
3.6 mmol). The mixture was stirred at room temperature for one hour. The
solvent was evaporated,
and the residue was purified by flash column chromatography (Silica gel,
methanol/methylene
chloride 4%/96%) to give N43-(2,6-dioxo-piperidin-3-y1)-2-methyl-4-oxo-3,4-
dihydro-quinazolin-
6-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (500 mg, 71%
yield); HPLC,
Waters Symmetry C18, 511m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%
H3PO4, gradient
to 95/5 in 5 min, kept for 5 min, 6.40 mm (99.5%); mp, 165-167 C;1HNMR (DMSO-
d6) 5 2.15-
2.20 (m, 1H, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.60 (d, J = 5 Hz, 2H,
CH2NH), 5.26 (dd, J =
6, 11 Hz, 111, CH), 7.458-8.04 (m, 7H, Ar), 9.28 (t, J = 5 Hz, 111, CH2NH),
11.02 (s, 1H, NH); 13C
NMR (DMSO-d6) 5 20.90, 23.40, 30.60, 42.35, 56.53, 119.93 (q, Jc-F = 257 Hz),
120.01, 120.67,
123.87, 126.62, 129.56, 133.19, 134.17, 134.07, 137.97, 145.83, 150.35,
154.61, 160.43, 165.06,
169.45, 172.59. LCMS MH = 489; Anal Calcd For C23H19N405F3+ 1.1 H20: C, 54.36;
H, 4.20;N,
11.02; F, 11.21. Found: C, 54.40; H, 3.89;N, 10.67; F, 11.06.
5.26 3,4-DICHLORO-N43-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-
3,4-MilYDRO-QUINAZOLINT-6-YLMETHYL1-BENZAMIDE
CI
= N
0 * 0 0
To a stirred suspension of 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-y1)-

piperidine-2,6-dione hydrogen chloride (0.45 g, 1.4 mmol) in acetonitrile (10
mL), was added 3,4-
dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N, N-diisopropyl ethylamine
(0.54 mL, 3.2
mmol). The mixture was stirred at room temperature for 15 minutes. The solvent
was evaporated,
and the residue was purified by flash column chromatography (Silica gel,
methanol/methylene
chloride 4%/96%) to give 3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-y1)-2-methyl-
4-oxo-3,4-
dihydro-quinazolin-5-ylmethyl]-benzamide as an off-white solid (290 mg, 46%
yield); HPLC,
Waters Symmetry C18, 511.m, 3.9 x 150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1%
H3PO4, gradient
to 95/5 in 5 min, kept for 5 min, 6.45 min (99.6%); mp, 177-179 C;'INMR (DMSO-
d6) 5 2.16-
2.18 (m, 1H, CHH), 2.56-2:84 (m, 6H, CHCH2, CH3), 4.59 (d, J = 5 Hz, 2H,
CH2NH), 5.26 (dd, J =
5, 9 Hz, 1H, Cl]), 7.58-8.14 (m, 6H, Ar), 9.34(t, J = 5 Hz, 1H, CH2NH), 11.02
(s, 1H, NH); 13C
NMR (DMSO-d6) 5 20.91, 23.41, 30.61, 42.47, 56.54, 120.01, 124.04, 126.66,
127.56, 129.20,
130.77, 131.32, 134.17, 134.37, 137.71, 145.88, 154.65, 160.42, 164.00,
169.45, 172.60. LCMS MH

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
= 473, 475; Anal Calcd For C22H18N404C12+ 1.0 CH2C12: C, 53.78; 11,4.10; N,
11.40; Cl, 14.43.
Found: C, 53.44; H, 4.11; N, 11.27; CI, 14.80.
5.27 N-113-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-MHYDRO-
QUINAZOLIN-6-YLMETHYL1-4-TRIFLUOROMETHYL-BENZAMIDE
F F 0
0 0
*
0
N
To a stirred solution of 4-trifluoromethyl-benzoic acid (0.30 g, 1.6 mmol) in
DMF
(8 mL) in a 40 C oil bath, was added 1.1' carbonyldiimidazole (0.29 g, 1.8
mmol), and the mixture
was stirred for one hour. Then 3-(6-aminomethy1-2-methy1-4-oxo-4H-quinazolin-3-
y1)-piperidine-
2,6-dione hydrogen chloride (0.54 g, 1.6 mmol) was added, and the mixture was
stirred for 15
minutes. The solvent was evaporated, and the residue was purified by flash
column chromatography
(Silica gel, methanol/methylene chloride 4%/96%) to give N43-(2,6-dioxo-
piperidin-3-y1)-2-
methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-benzamide as
an off-white
solid (500 mg, 67% yield); HPLC, Waters Symmetry C18, 5p..m, 3.9 x 150 mm, 1
mL/min, 240 nm,
10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.33 min (99.1%);
mp, 221-223 C;
1HNMR (DMSO-d6) 5 2.14-2.20 (m, 111, CHH), 2.56-2.88 (m, 6H, CHCH2, CH3), 4.62
(d, J = 5 Hz,
2H, CH2NH), 5.26 (dd, J = 6, 11 Hz, 111, Cl]), 7.59-8.11 (m, 711, Ar), 9.40
(t, J = 5 Hz, 1H,
CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) 5 20.90, 23.41, 30.60, 42.41,
56.53, 120.03,
123.90 (q, Jc-F = 253 Hz), 123.95, 125.36 (d, JC-F = 3 Hz), 125.45 (d, Jc-F =
3 Hz), 126.65, 128.14,
131.23 (d, Jc_F = 31 Hz), 134.11, 137.83, 145.87, 154.64, 160.42, 165.12,
169.45, 172.59. LCMS
MH = 473; Anal Calcd For C23H191\1404F3: C, 58.48; H, 4.05; N, 11.86; F,
12.06. Found: C, 58.36;
H, 3.96; N, 11.75; F, 11.84.
5.28 3-(2,7-DIMETHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-
DIONE
o 0 N 0
NI,
N
To a stirred mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol) and
imidazole (1.1 g, 16 mmol) in acetonitrile (20 mL), was added acetyl chloride
(1.1 mL, 16 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13 mmol),
imidazole (2.0 g, 30
mmol) and triphenyl phosphite (4.2 mL, 16 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(2,7-dimethy1-4-
oxo-4H-quinazolin-3-
y1)-piperidine-2,6-dione as a white solid (2.52 g, 67% yield): HPLC: Waters
Symmetry C18, 5 m,
61

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
3.9 x 150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.13 min (99.9 %); mp:
305 C
(decomp); 'H NMR (DMSO-d6) 8 2.08-2.24 (m, 1H, CUR), 2.45 (s, 3H, CH3), 2.56-
2.75 (m, 5H,
CH3, 2CHH), 2.81-2.91 (m, 1H, CHH), 5.24 (dd, J = 6, 11 Hz, 1H, NCH), 7.32
(dd, J = 1, 8 Hz 1H,
Ar), 7.43 (s, 1H, Ar), 7.91 (d, J = 8 Hz, 1H, Ar), 11.00 (s, 1H, NH); 13C NMR
(DMSO-d6) 8 21.00,
21.35, 23.45, 30.61, 56.43, 117.94, 125.80, 126.10, 127.97, 145.21, 146.98,
154.96, 160.34, 169.56,
172.62; LCMS: MH = 286; Anal Calcd for Ci5Hi5N303: C, 63.15; H, 5.21; N,
14.73. Found: C,
63.14; H, 5.21; N, 14.76.
5.29 3-(7-FLUOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
N
N=c _________________________________
To a stirred mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol) and
imidazole (1.3 g, 19 mmol) in acetonitrile (25 mL), was added acetyl chloride
(1.4 mL, 19 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (2.7 g, 16 mmol),
imidazole (2.4 g, 36
mmol) and triphenyl phosphite (5.1 mL, 19 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(7-fluoro-2-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (2.5 g, 52% yield):
HPLC: Waters Symmetry
C18, 5p.m, 3.9 x 150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 3.83 min
(100 %); rnP:
243-245 C; 1H NNW (DMSO-d6) 62.15-2.22 (m, 1H, CUR), 2.58-2.71 (m, 5H, CH3,
2C1-IH), 2.79-
2.86 (m, 1H, CHH), 5.28 (dd, J = 5, 11 Hz, 1H, NCH), 7.34-7.44 (m, 2H, Ar),
8.10 (dd, J = 6, 9 Hz,
1H, Ar), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) 8 20.89, 23.50, 30.58, 56.59,
111.62 (d, Jc-F = 22
Hz), 115.26 (d, Jc-F = 24 Hz), 117.32, 129.19 (d, Jc-F = 11 Hz), 148.97 (d,
Jc_F = 13 Hz), 156.65,
159.77, 165.83 (d, Jc-F. = 252 Hz), 169.41, 172.59; LCMS: MU = 290; Anal Calcd
for Ci4HuN303F:
C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 58.09; H, 4.08; N, 14.42; F,
6.72.
5.30 3-(7-CHLOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
o_o_tENi
cl
N
N=c _________________________________
To a stirred mixture of 2-amino-4-chlorobenzoic acid (5.0 g, 29 mmol) and
imidazole (2.4 g, 35 mmol) in acetonitrile (50 mL), was added acetyl chloride
(2.5 mL, 35 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (4.8 g, 29 mmol),
imidazole (4.4 g, 64
mmol) and triphenyl phosphite (8.4 mL, 32 mmol) and heated to reflux for 22
hours. The
62

CA 02704710 2010-03-23
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suspension was filtered and washed with acetonitrile (50 mL) and water (2 X 50
mL) to give 3-(7-
chloro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione as a white
solid (6.5 g, 73% yield):
HPLC: Waters Symmetry C18, 511m, 3.9 x 150 mm, 1 mL/min, 240 nm, 30/70
CH3CN/0.1% H3PO4,
4.36 min (99.9 %); mp: 291-293 C; 'H NMR (DMSO-d6) 8 2.16-2.23 (m, 1H, CHH),
2.59-2.72 (m,
5H, CH3, 2CHH), 2.79-2.92 (m, 1H, CHH), 5.29 (dd, J = 5, 11 Hz, 1H, NCH), 7.53
(dd, J= 2, 9 Hz,
1H, Ar), 7.69 (d, J = 8 Hz, 1H, Ar), 8.03 (d, J = 8 Hz, 1H, Ar), 11.07 (s, 1H,
NH); 13C NMR
(DMSO-d6) 620.84, 23.53, 30.58, 56.65, 19.06, 125.70, 126.91, 128.07, 139.30,
147.89, 156.74,
159.89, 169.35, 172.58; LCMS: MH = 306, 308; Anal Calcd for C141112N3030: C,
55.00; H, 3.96;
N, 13.74; Cl, 11.60. Found: C, 55.24; H, 3.78; N, 13.74; Cl, 12.01.
5.31 3-(7-BROM0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
0 0 N 0
Br 40
To a stirred mixture of 2-amino-4-bromobenzoic acid (2.0 g, 9.3 mmol) and
imidazole (0.8 g, 11 mmol) in acetonitrile (20 mL), was added acetyl chloride
(0.8 mL, 11 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (1.5 g, 9.3 mmol),
imidazole (1.4 g, 20
mmol) and triphenyl phosphite (2.9 mL, 11 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (30 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(7-bromo-2-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (2.4 g, 75% yield):
HPLC: Waters Symmetry
m, 3.9 x 150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 18.65 min (98.9 %);
mp:
315-317 C; IHNMR (DMSO-d6) 8 2.08-2.22 (m, 1H, CHH), 2.62-2.79 (m, 5H, CH3,
2CHH), 2.80-
2.91 (m, 1H, CHH), 5.28 (dd, J = 6, 11 Hz, 1H, NCH), 7.66 (dd, J = 2, 8 Hz,
111, Ar), 7.84 (d, J = 2
Hz 2H, Ar), 7.95 (d, J = 8 Hz, 1H, Ar), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) 8
20.83, 23.53,
24.02, 30.58, 56.67, 119.36, 128.06, 128.29, 128.80, 129.67, 147.93, 156.69,
160.02, 169.33,
172.57; LCMS: MH = 350, 352; Anal Calcd for CI4Hi2N303Br: C, 48.02; H, 3.45;
N, 12.00; Br,
22.82. Found: C, 47.94; H, 3.17; N, 11.85; Br, 20.65.
5.32 3-(2-METHYL-4-0X0-7-TRIFLUOROMETHYL-4H-OUINAZOLIN-3-YL)-
PIPERIDINE-2,6-DIONE
0 0 N 0
F F e N
To a stirred mixture of 2-amino-4-(trifluoromethyl)benzoic acid (3.0 g, 15
mmol)
and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), was added acetyl
chloride (1.3 mL, 18
63

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
mmol) at room temperature. The mixture was stirred at room temperature
overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15
mmol), imidazole
(2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) and heated to
reflux for 22 hours. To
the mixture, was added water (100 mL). The suspension was filtered and washed
with water (2 X
50 mL), ethyl acetate (2 X 50 mL), sodium hydrogen carbonate (sat, 50 mL) and
water (50 mL) to
give a white solid, which was dissolved in DMS0 (10 mL). To the solution, was
added water (3
mL) to give a suspension. The suspension was filtered and washed with DMS0 (2
mL) to give a
white solid. The solid was stirred in water (50 mL) at 60 C for 2hours, then
at room temperature
overnight. The suspension was filtered and washed with water (2 X 50 mL) to
give 3-(2-methy1-4-
oxo-7-trifluoromethy1-4H-quinazolin-3-y1)-piperidine-2,6-dione as a white
solid (1.17 g, 24%
yield): HPLC: Waters Symmetry CB, 5pm, 3.9 x 150 mm, 1 mL/min, 240 nm, 30/70
CH3CN/0.1%
H31304, 8.14 min (99.9 %); mp: 277-279 C; NMR (DMSO-d6) 8 2.18-2.25 (m, 1H,
CHB), 2.59-
2.74 (m, 5H, CH3, 2CHH), 2.81-2.88 (m, 1H, CHIT), 5.34 (dd, J = 6, 11 Hz, 1H,
NCH), 7.80 (dd, J =
2, 8 Hz, 1H, Ar), 7.96 (s, 1H, Ar), 8.24 (d, J = 8 Hz, 1H, Ar), 11.09 (s, 1H,
Nil); 13C NMR (DMSO-
d6) 8 20.73, 23.54, 30.57, 56.82, 122.30 (q, Jc_F = 3 Hz), 122.99, 123.45 (q,
Jc-F = 273 Hz), 123.74
(q, JC-F = 4 Hz), 127.85, 134.22 (q, Jc_F = 32 Hz), 146.84, 156.98, 159.80,
169.24, 172.56; LCMS:
MH = 340; Anal Calcd for Ci5Hi2N303F3: C, 53.10; H, 3.57; N, 12.39; F, 16.80.
Found: C, 52.55; H,
3.42;N, 12.21; F, 17.18.
5.33 3-(7-FLUOR0-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
0
N--N1.1 0
N=" _________________________________
Step 1: A mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol) and CDI
(2.4
g, 15 mmol) in acetonitrile (30 mL) was stirred at room temperature for 1.5
hours. To the
suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g,
15 mmol) and
sodium hydrogen carbonate (1.6 g, 19 mmol), and the mixture was heated at 50
C for 21 hours.
The suspension was cooled to room temperature for 1 hour. The suspension was
filtered and
washed with acetonitrile (5 mL) and water (2 X 20 mL). The solid was stirred
in methanol (15 mL)
overnight. The suspension was filtered and washed with methanol (15 mL) to
give 2-amino-N-(2,6-
dioxo-piperidin-3-y1)-4-fluorobenzamide as an off-white solid (1.9 g, 45%
yield): 'H NMR
(DMSO-d6) 8 1.91-1.96 (m, 1H, CHH), 2.04-2.18 (m, 1H, CI-111), 2.50-2.56 (m,
1H, CHH), 2.73-
2.85 (m, 1H, CHIT), 4.67-4.76 (m, 1H, NCH), 6.35 (dt, J = 2, 9 Hz, 1H, Ar),
6.48 (dd, J = 2, 12 Hz,
1H, Ar), 6.76 (brs, 2H, NH2), 7.58 (dd; J = 7, 8 Hz, 1H, Ar), 8.50 (d, J = 8
Hz, 1H, Ni]), 10.84 (s,
1H, NH); 13C NMR (DMSO-d6) 624.06, 30.91, 48.98, 101.30 (d, Jc.F = 23 Hz),
101.60 (d, Jc_F = 22
Hz), 110.60, 130.66 (d, Jc-F = 11 Hz), 152.16 (d, Jc_F = 12 Hz), 164.46 (d, Jc-
F = 246 Hz), 167.80,
172.30, 172.94.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-4-fluoro-benzamide
(0.9 g, 3.4 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic
acid (110 mg) was
64

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
heated to 160 C in a microwave oven for 15 minutes. To the mixture, was added
methanol (10
mL), and the mixture was stirred for 10 minutes. The suspension was filtered
and washed with
methanol to give 3-(7-fluoro-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione as
a white solid (650
mg, 70% yield): HPLC: Waters Symmetry C18, 5p.rn, 3.9 x 150 mm, 1 mL/min, 240
nm, 30/70
CH3CN/0.1% H3PO4, 2.45 min (96.1%); mp: 296-298 C; 1H NMR (DMSO-d6) 2.13-2.19
(m, 1H,
CHH), 2.63-2.73 (m, 2H, 2CHH), 2.82-2.93 (m, 111, CHH), 5.50 (br, 1H, NCH),
7.46 (dt, J = 3, 9
Hz, 1H, Ar), 7.53 (dd, J = 3, 10 Hz, 1H, Ar), 8.22 (dd, J = 6, 9 Hz, 1H, Ar),
8.42 (s, 1H, Cu), 11.18
(s, 1H, NH); 13C NMR (DMSO-d6) 8 22.45, 30.88, 56.43, 112.3 (d, Jc_F = 22 Hz),
115.91 (d, Jc-F =
23 Hz), 118.38, 129.32 (d, Jc-F. = 11 Hz), 148.71, 149.65 (d, Jc-F = 14 Hz),
159.00, 165.70 (d, Jc_F =
252 Hz), 169.76, 172.41; LCMS: MH = 276; Anal Calcd for C13H10N303F: C, 56.73;
H, 3.66; N,
15.27. Found: C, 56.39; H, 3.60; N, 15.16.
5.34 3-(7-METHYL-4-0X0-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
0 0
N-t1%10
Step 1: A mixture of 2-amino-4-methylbenzoic acid (2.0 g, 13 mmol) and CDI
(2.0
g, 12 mmol) in acetonitrile (20 mL) was stirred at room temperature for 1.5
hours. To the
suspension, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g,
12 mmol) and
sodium hydrogen carbonate (1.3 g, 16 mmol), and the mixture was heated at 50
C for 21 hours.
The suspension was cooled to room temperature for 1 hour. The suspension was
filtered and
washed with water (50 mL) and ethyl acetate (20 mL). The solid was dried in a
vacuum oven
overnight to give 2-amino-N-(2,6-dioxo-piperidin-3-y1)-4-methyl-benzamide as a
white solid (2.2 g,
69% yield): 1H NMR (DMSO-d6) 8 1.90-1.96 (m, 1H, CHH), 2.05-2.14 (m, 1H, CHH),
2.18 (s, 311,
CH3), 2.49-2.55 (m, 1H, CHH), 2.72-2.84 (m, 1H, CHI-0, 4.67-4.75 (m, 1H, NCH),
6.36 (dd, J =2, 8
Hz, 1H, Ar), 6.43 (br, 21-1, NHH, Ar), 6.51 (s, 1H, NHH), 7.43 (d, J = 8 Hz,
1H, Ar), 8.38 (d, J = 8
Hz, 1H, NH), 10.83 (s, 1H, NH); 13C NMR (DMSO-d6) 8 21.05, 24.21, 30.99,
48.97, 111.26,
115.74, 116.48, 128.09, 141.71, 149.96, 168.54, 172.50, 173.04; LCMS: MH= 262.
Step 2: A solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-4-methyl-benzamide
(1.0 g, 3.8 mmol) and trimethyl orthoformate (10 mL) and p-toluene sulfonic
acid (250 mg) was
heated to 160 C in a microwave oven for 30 minutes. The suspension was
filtered and washed with
methanol (20 mL), water (20 mL) and methanol (20 mL) to give 3-(7-methy1-4-oxo-
4H-quinazolin-
3-y1)-piperidine-2,6-dione as an off-white solid (880 mg, 85% yield): HPLC:
Waters Symmetry C18,
51.itn, 3.9 x 150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.14 min
(97.1%); mp: 313-
315 C; 11-1NMR (DMSO-d6) 8 2.11-2.18 (m, 111, CHH), 2.48 (s, 311, CH3), 2.61-
2.74 (m, 2H,
2CHH), 2.82-2.92 (m, 1H, CHH), 5.46 (br, 1H, NCH), 7.41 (dd, J = 1, 8 Hz, 1H,
Ar), 7.53 (s, 1H,
Ar), 8.03 (d, J = 8 Hz, 1H, Ar), 8.33 (s, 111, Cl]), 11.15 (s, 1H, NH); 13C
NMR (DMSO-d6) 621.23,
22.51, 30.91, 56.74, 118.95, 125.93, 126.74, 128.66, 145.27, 147.35, 147.59,
159.54, 169.88,

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
172.44; LCMS: MH = 272; Anal Calcd for Ci4lli3N303 + 0.1 H20: C, 61.58; H,
4.87; N, 15.39.
Found: C, 61.41; H, 4.87; N, 15.15.
5.35 347-AMINO-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
0 C:IN,N 0
N
I-12N
Step l: To a stirred mixture of 2-amino-4-nitrobenzoic acid (5.0 g, 28 mmol)
and
imidazole (2.2 g, 33 mmol) in acetonitrile (50 mL), was added acetyl chloride
(2.3 mL, 33 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (4.5 g, 28 mmol),
imidazole (4.1 g, 60
mmol) and triphenyl phosphite (8.7 mL, 33 mmol), and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(2-methy1-7-nitro-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as an off- white solid (4.8 g, 55%
yield): HPLC: Waters
Symmetry C18, 511m, 3.9 x 150 mm, 1 mL/min, 240 tun, 10/90 CH3CN/0.1% H3PO4,
5.69 min (95.4
%); IHNMR (DMSO-d6) 8 2.15-2.25 (m, 1H, CHH), 2.59-2.69 (m, 2H, 2CHH), 2.70
(s, 3H, CH3),
2.79-2.87 (m, 111, CHH), 5.35 (dd, J = 6, 12 Hz, 1H, NCH), 8.20-8.29 (m, 2H,
Ar), 8.34 (d, J = 2
Hz, 1H, Ar), 11.10 (s, 1H, NH); I3C NMR (DMSO-d6) 820.60, 23.53, 30.49, 56.85,
120.26, 121.58,
124.35, 128.30, 147.08, 151.30, 157.61, 159.52, 160.09, 172.48; LCMS: MH =
317.
Step 2: A suspension of 3-(2-methy1-7-nitro-4-oxo-4H-quinazolin-3-y1)-
piperidine-
2,6-dione (4.8 g, 13 mmol) and 20% Pd(OH)2/C (1.0 g) in cyclohexene (15 mL)
and DMF (60 mL)
was heated in a 125 C oil bath overnight. The suspension was filtered thru a
pad of Celite, and
washed with DMF (30 mL). To the filtrate, was added water (150 mL) to give a
suspension. The
suspension was filtered and washed with water (50 mL) to give 3-(7-amino-2-
methyl-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as an off-white solid (3.07 g, 71%
yield): HPLC: Waters
Symmetry Cig, 5 ,m, 3.9 x 150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min
CH3CN/0.1%
H3PO4, 4.08 min (97.3%) [sample was dissolved in 0.1% H3PO4]; mp: 305-307 C;
IH NMR
(DMSO-d6) 8 2.05-2.16 (m, 1H, CHH), 2.53 (s, 3H, CH3), 2.58-2.69 (m, 2H,
2CHH), 2.75-2.86 (m,
1H, CHH), 5.10 (dd, J = 6, 11 Hz, 1H, NCH), 6.11 (brs, 2H, NH2), 6.54 (d, J =
2 Hz, 1H, Ar), 6.68
(dd, J = 2, 8 Hz, 1H, Ar), 10.93 (s, 1H, NH); I3C NMR (DMSO-d6) 8 21.36,
23.43, 30.63, 55.97,
106.12, 109.17, 114.70, 127.28, 148.95, 154.42, 154.61, 159.85, 169.87,
172.67; LCMS: MH = 287;
Anal Calcd for Ci4H14N403: C, 58.74; H, 4.93; N, 19.57. Found: C, 58.60; H,
4.83; N, 19.40.
5.36 [3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-0X0-3,4-DIHYDRO-
OUINAZOLIN-7-YLMETHYL1-CARBAMIC ACID TERT-BUTYL ESTER
66

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
Y-0
0 0 H
N¨t_ti 0
0 N=c
Step 1: To a stirred solution of 4-methyl-2-nitro-benzoic acid methyl ester
(108.5 g,
555.7 mmol) in acetonitrile (750 mL), was added NBS (97.9 g, 550.1 mmol). The
mixture was
heated to a gentle reflex with a 200W light bulb on for 5.5 hours. The solvent
was evaporated, and
the residue was dissolved in ethyl acetate (1500 mL). The solution was washed
with water (2 x 600
mL) and brine (300 mL), dried over magnesium sulfate, and concentrated to give
a brown oil. To
the oil, was added t-butyl methyl ether (300 mL). The mixture was heated at 70
C for 15 minutes.
The mixture was allowed to cool to about 53 C over one hour, then to 45 C,
and then at 20-25 C,
while blowing nitrogen with a glass pipette overnight. The suspension was
filtered via a medium
pore-sized funnel. The solid was washed with a pre-cooled 10 C mixed solvent
of heptane/MTBE
(1/2 vol/vol) and suction dried in hood overnight to give 4-bromomethy1-2-
nitro-benzoic acid
methyl ester as an off-white solid (66 g, 43% yield). The solid was used in
the next step without
further purification.
Step 2: A stirred mixture of 4-bromomethy1-2-nitro-benzoic acid methyl ester
(66.3
g, 241.9 mmol), di-tert-butyl iminodicarboxylate (52.72 g, 242.6 mmol), cesium
carbonate (161.58
g, 495.9 mmol), and lithium iodide (1.62 g, 12 mmol) in 2-butanone (700 mL)
was heated to reflux
in a 100 C oil bath for 12 hours while stirred with a mechanical stirrer. The
mixture was allowed to
cool to room temperature. To the mixture, was added brine (300 mL), water (300
mL), and ethyl
acetate (600 mL), and the mixture was stirred for 10 minutes. The suspension
was filtered through a
pad of Celite. The two layers were separated, and the organic layer was
evaporated to a less
volume. The aqueous layer was extracted with ethyl acetate (2 x 150 mL). The
combined organic
layers were washed with brine (1 x 500 mL), dried over magnesium sulfate while
de-colored at the
same time by charcoal at room temperature with stirring for 30 minutes. The
black mixture was
filtered through a pad of Celite, and the filtrate was evaporated to give 4-
(di-tert-
butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as a brown oil
(96.0 g, 96.7%
yield). The product was used in the next step without further purification.
Step 3: To a stirred brown solution of 4-(di-tert-butoxycarbonylamino-methyl)-
2-
nitro-benzoic acid methyl ester (95.97 g, 233.8 mmol) in methylene chloride
(800 mL), was added
trifluoroacetic acid (33.87 mL, 455.9 mmol), and the mixture was stirred at
room temperature
overnight. Sat. sodium bicarbonate (500 mL) was added to the solution, and the
mixture was stirred
for 10 minutes. The organic layer was separated, dried over magnesium sulfate,
and evaporated to
give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester as
a brown oil (64.36 g,
88% crude yield). The product was used in the next step without further
purification.
Step 4: A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid
methyl ester (64.36 g, 207.4 mmol), lithium hydroxide (5.96 g, 248.9 mmol) in
methanol (500 mL)
and water (250 mL) was stirred with a mechanical stirrer at room temperature
overnight. The
methanol was evaporated, and to the aqueous solution, was added 1 N HC1 (300
mL) to form the
67

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
precipitate. Ether (350 mL) was added, and the mixture was stirred at 0 C for
2 hours. No desired
precipitation was formed. The mixture was evaporated. To the mixture, was
added water (500 mL).
The aqueous layer was extracted with ethyl acetate (5 x 120 mL). The combined
organic layers
were separated, dried over magnesium sulfate, and concentrated to give 4-(tert-

butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil (56.69 g, 92%
yield). The
product was used in the next step without further purification.
Step 5: A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid
(56.57, 190.9 mmol) in methanol (250 mL) and palladium/carbon (5.66 g, 10%
weight) was
hydrogenated with a Parr-shaker overnight at 51 psi. The black mixture was
filtered through a pad
of Celite, and the filtrate was evaporated to give a brown oil, which was
stirred in ether (300 mL)
overnight. The ether slurry was filtered to give 2-amino-4-(tert-
butoxycarbonylamino-methyl)-
benzoic acid as a brown solid (42.0 g, 84% yield). The product was used in the
next step without
further purification.
Step 6: To a stirred solution of 2-amino-4-(tert-butoxycarbonylamino-methyl)-
benzoic acid (24.75 g, 92.94 mmol), imidazole (7.59 g, 111.53 mmol) in
acetonitrile (300 mL), was
added acetyl chloride (7.96 mL, 111.53 mmol), and the mixture was stirred at
room temperature
overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen
chloride (15.30 g,
92.94 mmol), imidazole (12.66 g, 185.89 mmol) and triphenyl phosphite (29.23
mL, 111.53 mmol),
and the mixture was heated to reflux for 6 hours. The mixture was cooled to
room temperature and
the brown mixture was filtered. The filtrate was evaporated and then purified
by flash column
chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give [3-
(2,6-dioxo-piperidin-
3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-7-ylmethyl]-carbamic acid tert-
butyl ester as a light
yellow solid (24.57 g, 66% yield); HPLC, Waters Symmetry C18, 5 m, 3.9 x 150
mm, 1 mL/min,
240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 5.97 min
(99.7%); mp, 240-
242 C; IHNMR (DMSO-d6) 1.29 (brs, 1H, CH from the BOC group), 1.40 (s, 8H, 8CH
from the
BOC group), 2.11-2.19 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH3), 4.26 (d, J
= 6 Hz, 2H,
CH2NH), 5.25 (dd, J = 5, 11 Hz, 1H, Cl]), 7.35-7.99 (m, 4H, Ar and NHCH2),
11.02 (s, 1H, NH);
13C NMR (DM50-d6) 8 20.97, 23.49, 28.19, 30.60, 43.22, 56.48, 78.00, 118.84,
123.99, 125.41,
126.00, 146.93, 147.55, 155.15, 155.81, 160.29, 169.51, 172.61. LCMS MH = 401;
Anal Calcd For
C20H24N405: C, 59.99; H, 6.04; N, 13.99. Found: C, 59.78; H, 5.78; N, 13.85.
5.37 3-(7-AMINOMETHYL-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-
PIPERIDINE-2,6-DIONE HYDROGEN CHLORIDE
H-Cl
0 0
H2N
N=
Step 1: To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-
4-
oxo-3,4-dihydro-quinazolin-7-ylmethy1]-carbamic acid tert-butyl ester (14.7 g,
36.8 mmol) in
68

CA 02704710 2015-03-19
53686-95
methanol (200 mL) and methylene chloride (200 mL), was added 2 M HCI in ether
(320 mL), and
the mixture was stirred overnight. The solverdwas evaporated, and the residue
was stirred in ether
(100 mL) for 2 hours. The suspension was filtered to give 3-(7-aminomethy1-2-
methy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione hydrogen chloride as a light yellow
solid (13.2 g, 106% crude
yield). The product was used in the next step without further purification.
Step 2: 3-(7-Aminomethy1-2-methyl-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione hydro-chloride (1.00 g) was dissolved in water (100 mL). The solution
was washed with ethyl
acetate (2 x 100 mL). The aqueous layer was evaporated to give 3-(7-
aminomethy1-2-methy1-4-oxo-
4H-quinazolin-3-y1)-piperidine-2,6-dione hydrogen chloride as an off-white
solid (0.86 g, 86%
TM
yield); HPLC, Waters Xterta RP 18, 5gm, 3.9 x 150 mm, 1 mL/min, 240 nm, Waters
LC Module 1,
05/95 CH3CN/0.1% (HCO2)NH4, 6.27 min (98.7%); mp, 313-315 C;1HNMR (DMSO-d6)
2.17-
2.24 (m, 1H, CHH), 2.58-2.89 (m, 6H, CHCH2, CH3), 4.20 (q, J = 5 Hz, 2H,
ArCH2), 5.34 (dd, J = 6,
11 Hz, 1H, Cl!, hiding under the water peak), 7.64-8.09 (m, 3H, Ar), 8.72
(bra, 3H, C1NH3), 11.07
(s, 111, NH); 13C NMR (DMSO-d6) 8 20.88, 22.97, 30.57, 41.69, 56.71, 119.61,
125.38, 126.42,
127.25, 141.34, 145.36, 156.66, 159.83, 169.25, 172.57. LCMS MH = 301; Anal
Calcd For
C151112N403C1+ 1.0 H20 and + 0.9 HCI: C, 4648; H, 5.17; N, 14.45; Cl, 17.38.
Found: C, 46.68; H,
5.15;N, 14.32; Cl, 17.05.
5.38 3(2.8-DIMETHYL-4-0X04H-OUINAZOLIN-3-YL)-PIPERIMINE-2,6-
DIONE
00 II 0
y
To a stirred mixture of 2-amino-3-methylbenzoic acid (3.0 g, 20 mmol) and
imidazole (1.6 g, 24 mmol) in acetonitrile (30 mL), was added acetyl chloride
(1.7 mL, 24 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (3.3 g, 20 mmol),
imidazole (3.0 g, 68
mmol) and triphenyl phosphite (6.2 mL, 24 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 100
mL), ethyl acetate (2 X 100 mL), sodium hydrogen carbonate (sat, 100 mL) and
water (100 mL) to
give a white solid, which was stirred in DMSO (20 mL) at 65 C. The mixture
was polished filtered
and washed with DMSO (10 mL). To the filtrate, was added water (100 mL) to
give a suspension.
The suspension was filtered and washed with water (2 X 50 mL) to give 3-(2,8-
dimethy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (3.2 g, 56% yield):
HPLC: Waters Symmetry
m, 3.9 x 150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 5.85 min (99.6 %);
mP:
296-298 C; IHNMR (DMSO-d6) 8 2.12-2.24 (m, 1H, CH.H), 2.51 (s, 3H, CH3), 2.48-
2.74 (m, 2H,
2CHH), 2.66 (s, 3H, CH3), 2.76-2.91 (m, 1H, CHH), 5.27 (dd, J = 6, 11 Hz, 1H,
NCH), 7.38 (t, J = 8
Hz, 1H, Ar), 7.67 (d, J = 7 Hz, 111, Ar), 7.86 (dd, J = 0.6, 8 Hz, 1H, Ar),
11.02 (s, 1H, NH); '3C
69

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
NMR (DMSO-d6) 8 16.91, 20.91, 23.80, 30.60, 56.51, 120.23, 123.59, 126.05,
134.72, 134.94,
145.25, 153.82, 160.71, 169.51, 172.62; LCMS: MU = 286; Anal Calcd for
Ci5H15N303 + 0.2 H20:
C, 62.36; H, 5.37;N, 14.54. Found: C, 62.21; H, 5.31;N, 14.43.
5.39 3-(8-FLUOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
0 N 0
0
To a stirred mixture of 2-amino-3-fluorobenzoic acid (3.0 g, 19 mmol) and
imidazole (1.6 g, 23 mmol) in acetonitrile (30 mL), was added acetyl chloride
(1.7 mL, 23 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (3.2 g, 19 mmol),
imidazole (2.9 g, 43
mmol) and triphenyl phosphite (6.1 mL, 23 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give a white solid, which
was purified with
preparative HPLC (C18 20/80 CH3CN/H20) to give a white solid. The white solid
in DMSO (20
mL) was heated at 60 C for 30 minutes. To the solution, was added water (10
mL). The
suspension was cooled to room temperature. The suspension was filtered and
washed with DMSO
(4 mL) and water (20 mL) to give 3-(8-fluoro-2-methy1-4-oxo-4H-quinazolin-3-
y1)-piperidine-2,6-
dione as a white solid (3.11 g, 67% yield): HPLC: Waters Symmetry Cig, 5p.m,
3.9 x 150 mm, 1
mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.7 min (99.7 %); mp: 305 C (decomp);
1H NMR
(DMSO-d6) 8 2.16-2.23 (m, 1H, CHIT), 2.43-2.76 (m, 511, CH3, 2CHH), 2.79-2.92
(m, 1H, CHH),
5.32 (dd, J = 6, 11 Hz, 1H, NCH), 7.46-7.53 (m, 1H, Ar), 7.67-7.73 (m, 1H,
Ar), 7.84-7.94 (m, 1H,
Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) 520.80, 23.67, 30.58, 56.71, 120.04
(d, Jc-F = 19 Hz),
121.71 (d, Jc_F = 4 Hz), 122.31, 126.91 (d, Jc-F = 8 Hz), 136.04 (d, Jc_F = 12
Hz), 155.93 (d, JC-F =
254 Hz), 155.93, 159.62 (d, Jc-F = 3 Hz), 169.32, 172.57; LCMS: MH = 290; Anal
Calcd for
Ci4H12N303F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 57.87; H, 3.94;
N, 14.35; F, 6.91.
5.40 3-(8-CHLOR0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
0 0 N 0
CI
To a stirred mixture of 2-amino-3-chlorobenzoic acid (2.2 g, 13 mmol) and
imidazole (1.1 g, 16 mmol) in acetonitrile (30 mL), was added acetyl chloride
(1.1 mL, 16 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol),
imidazole (1.9 g, 28
mmol) and triphenyl phosphite (4.0 mL, 15 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give a white solid, which
was stirred in
methanol (50 mL) overnight. The suspension was filtered and washed with
methanol (30 mL) and
water (30 mL) to give 3-(8-chloro-2-methy1-4-oxo-4H-quinazolin-3-y1)-
piperidine-2,6-dione as a
white solid (1.5 g, 38% yield): HPLC: Waters Symmetry C18, 51.tm, 3.9 x 150
mm, 1 mL/min, 240
nm, 25/75 CH3CN/0.1% H3PO4, 6.51 min (99.6 %); mp: 290-292 C; 'H NMR (DMSO-
d6) 8 2.16-
2.23 (m, 1H, CHH), 2.59-2.69 (m, 5H, CH3, 2CHH), 2.79-2.87 (m, 1H, CHIT), 5.32
(dd, J = 5, 11
Hz, 1H, NCH), 7.48 (t, J = 8 Hz, 1H, Ar), 7.96-8.02 (m, 2H, Ar), 11.07 (s, 1H,
NH); 13C NMR
(DMSO-d6) 620.68, 23.75, 30.51, 56.68, 121.87, 125.08, 126.91, 130.03, 134.69,
143.14, 156.14,
159.88, 169.23, 172.51; LCMS: MH = 306, 308; Anal Calcd for Ci4HuN303C1: C,
55.00; H, 3.96;
N, 13.74; Cl, 11.60. Found: C, 54.73; H, 3.96;N, 13.58; Cl, 11.03.
5.41 3-(8-BROM0-2-METHYL-4-0X0-4H-OUINAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
H
0 N 0
0 y.
40 _.r\il
Br
To a stirred mixture of 2-amino-3-bromobenzoic acid (1.0 g, 4.6 mmol) and
imidazole (0.38 g, 5.5 mmol) in acetonitrile (10 mL), was added acetyl
chloride (0.6 mL, 8.3 mmol)
at room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (0.76 g, 4.6 mmol),
imidazole (0.7 g, 10
mmol) and triphenyl phosphite (1.5 mL, 5.6 mmol) and heated to reflux for 22
hours. To the
mixture, was added water (60 mL). The suspension was filtered and washed with
water (2 X 50
mL), ethyl acetate (2 X 50 mL), and water (50 mL) to give 3-(8-bromo-2-methy1-
4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione as a white solid (0.34 g, 21% yield):
HPLC: Waters
Symmetry CB, 5p.m, 3.9 x 150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4,
9.47 min (99.6
%); mp: 307-309 C; Ili NMR (DMSO-d6) 8 2.16-2.23 (m, 1H, CHH), 2.58-2.67 (m,
2H, 2CHH),
2.68 (s, 3H, CH3), 2.76-2.92 (m, 1H, CHH), 5.31 (dd, J = 5, 11 Hz, 1H, NCH),
7.41 (t, J = 8 Hz, 1H,
Ar), 8.04 (dd, J = 2, 8 Hz 1H, Ar), 8.15 (dd, J = 1, 8 Hz 1H, Ar), 11.07 (s,
1H, NH); 13C NMR
(DMSO-d6) 620.73, 23.85, 30.57, 56.76, 121.09, 121.82, 125.86, 127.47, 138.08,
144.23, 156.23,
159.97, 169.29, 172.58; LCMS: MH = 350, 352; Anal Calcd for C141-112N303Br: C,
48.02; H, 3.45;
N, 12.00; Br, 22.82. Found: C, 47.74; H, 3.23; N, 11.85; Br, 22.42.
71

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
5.42 3-(8-HYDROXY-2-METHYL-4-0X0-4H-QUINAZOLINT-3-YL)-
PIPERIDINE-2,6-DIONE
H
0 0-N,r0
0 y-
OH
To a stirred mixture of 2-amino-3-hydroxybenzoic acid (2.0 g, 13.1 mmol) and
imidazole (2.0 g, 29.4 mmol) in acetonitrile (30 mL), was added acetyl
chloride (2.0 mL, 28.7
mmol) at room temperature. The mixture was stirred at room temperature
overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13.1
mmol), imidazole
(2.0 g, 29.4 mmol) and triphenyl phosphite (4.11 mL, 15.7 mmol) and heated to
reflux for 22 hours.
To the mixture, was added water (60 mL) and conc HC1 until pH ¨1. The solvent
was removed in
vacuo. To the residue, was added water (50 mL). The aqueous layer was
extracted with ethyl
acetate (2 X 50 mL). To the aqueous layer, was added sodium hydrogen carbonate
(1.8 g) to pH =
7-8, and the mixture was stirred at room temperature to give a suspension. The
suspension was
filtered to give 3-(8-hydroxy-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-
2,6-dione as an off-
white solid (0.6 g, 16% yield): HPLC: Waters Symmetry C18, 5ii.m, 3.9 x 150
mm, 1 mL/min, 240
nm, 20/80 CH3CN/0.1% H3PO4, 3.03 min (99.3 %); mp: 266-268 C; IH NMR (DMSO-
d6) 8 2.10-
2.22 (m, 1H, CHH), 2.57-2.72 (m, 5H, CH3, 2CHH), 2.78-2.92 (m, 1H, CHB), 5.25
(dd, J = 5, 11
Hz, 1H, NCH), 7.19 (dd, J = 1, 8 Hz, 111, Ar), 7.30 (t, J = 8 Hz, 1H, Ar),
7.45 (dd, J = 1, 8 Hz, 1H,
Ar), 9.65 (s, 1H, 01/), 11.02 (s, 1H, NH); I3C NMR (DMSO-d6) 8 20.92, 23.37,
30.59, 56.45,
115.62, 118.51, 121.19, 127.05, 135.91, 152.34, 153.09, 160.45, 169.52,
172.62; LCMS: MH = 288;
Anal Calcd for C141-113N304+ 1 H20: C, 55.08; H, 4.95; N, 13.76. Found: C,
54.88; H, 4.97; N,
13.77.
5.43 3-(2-METHYL-4-0X0-8-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-
PIPERIDINE-2,6-DIONE
H
0 0 N 0
----.__.--'
40) y
N.
F F
F
To a stirred mixture of 2-amino-3-(trifluoromethyl)benzoic acid (2.0 g, 9.8
mmol)
and imidazole (0.8 g, 12 mmol) in acetonitrile (20 mL), was added acetyl
chloride (0.83 mL, 12
mmol) at room temperature. The mixture was stirred at room temperature
overnight. To the
mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (1.6 g, 9.8
mmol), imidazole
(1.5 g, 22 mmol) and triphenyl phosphite (3.1 mL, 12 mmol) and heated to
reflux for 22 hours. To
the mixture, was added water (60 mL). The suspension was filtered and washed
with water (2 X 50
mL), ethyl acetate (2 X 50 mL), sodium hydrogen carbonate (sat, 50 mL) and
water (50 mL) to give
3-(2-methy1-4-oxo-8-trifluoromethy1-4H-quinazolin-3-y1)-piperidine-2,6-dione
as a white solid
72
=

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
(0.32 g, 10% yield): HPLC: Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min,
240 nm, 35/65
CH3CN/0.1% H31304, 7.57 min (99.8 %); mp: 351-353 C; IH NMR (DMSO-d6) 82.19-
2.26 (m, 1H,
CHH), 2.59-2.70 (m, 5H, CH3, 2CHH), 2.81-2.93 (m, 1H, CHH), 5.34 (dd, J = 5,
11 Hz, 1H, NCH),
7.64 (t, J = 8 Hz, 1H, Ar), 8.20 (d, J = 8 Hz 1H, Ar), 8.31 (d, J = 8 Hz, 1H,
Ar), 11.09 (s, 1H, NH);
13C NMR (DMSO-d6) 620.67, 24.05, 30.57, 56.84, 121.48, 123.52 (q, Jc-F = 274
Hz), 124.77 (q, JC-F
=30 Hz), 125.98, 130.74, 132.29 (q, Jc-F 5 Hz), 144.20, 156.71, 159.68,
169.28, 172.58; LCMS:
MH = 340; Anal Calcd for Ci5H12N303F3+ 0.3 H20 + 0.1 CH3CN: C, 52.34; H, 3.72;
N, 12.45; F,
16.34. Found: C, 52.71; H, 3.52; N, 12.31; F, 15.99.
5.44 3-(8-METHYL-4-0X0-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE
N 0
Step 1: A mixture of 2-amino-3-methylbenzoic acid (2.1 g, 14 mmol) and CDI
(1.9
g, 12 mmol) in acetonitrile (25 mL) was stirred at room temperature for 5
hours. To the suspension,
was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.3 g, 14 mmol),
triethylamine (7.2
mL, 66 mmol) and acetic acid (8 mL, 132 mmol), and the mixture was heated to
reflux for 16 hours.
To the mixture, was added water (75 mL) and stirred at room temperature for 2
hours. The
suspension was filtered and washed with water (50 mL) and ethyl acetate (20
mL) to give 2-amino-
N-(2,6-dioxo-piperidin-3-y1)-3-methyl-benzamide as a white solid (1.9 g, 61%
yield): 1HNMR
(DMSO-d6) 8 1.92-1.99 (m, 1H, CHH), 2.06 (s, 3H, CH3), 2.04-2.14 (m, 111,
CHH), 2.51-2.56 (m,
1H, Cu]), 2.73-2.85 (m, 1H, CHH), 4.69-4.78 (m, 1H, NCH), 6.22 (brs, 2H, NH2),
6.50 (t, J = 8
Hz, 1H, Ar), 7.10 (d, J = 8 Hz, 1H, Ar), 7.40 (d, J = 8 Hz, 1H, Ar), 8.47 (d,
J = 8 Hz, 1H, NH), 10.83
(s, 1H, NH); LCMS: MH= 262.
Step 2: A stirred solution of 2-amino-N-(2,6-dioxo-piperidin-3-y1)-3-methyl-
benzamide (0.9 g, 3.4 mmol) and trimethyl orthoformate (4.5 mL) and p-toluene
sulfonic acid (250
mg) in acetonitrile (20 mL) was heated to reflux for 17hours. To the mixture,
was added water (75
mL) and stirred for 20 minutes. The suspension was filtered and washed with
methanol (20 mL),
water (20 mL) and ethyl acetate (20 mL) to give a purple solid. The solid in
NMP (4 mL) was
heated at 80 C for 30 minutes. To the solution, was added water (1 mL), and
the mixture was
allowed to cool to room temperature. The suspension was filtered and washed
with water (30 mL)
to give 3-(8-methyl-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione as a light
purple solid (660 mg,
72% yield): HPLC: Waters Symmetry C18, 5 m, 3.9 x 150 mm, 1 mL/min, 240 nm,
30/70
CH3CN/0.1% H3PO4, 3.07 min (98.6%); mp: 290-292 C; IH NMR (DMSO-d6) 8 2.11-
2.19 (m, 1H,
CHH), 2.56 (s, 3H, CH3), 2.62-2.93 (m, 3H, CH2, CHH), 5.48 (br, 1H, NCH), 7.46
(t, J = 8 Hz, 1H,
Ar), 7.73 (d, J = 8 Hz, 1H, Ar), 7.99 (d, J = 8 Hz, 1H, Ar), 8.38 (s, 1H, CH),
11.16 (s, 1H, NH); 13C
NMR (DMSO-d6) 8 17.01, 22.53, 30.97, 56.22, 121.36, 123.79, 126.51, 126.86,
135.03, 135.47,
136.39, 145.96, 146.36, 159.97, 169.92, 172.52; LCMS: MH = 272; Anal Calcd for
C141-113N303: C,
61.99; H, 4.83; N, 15.49. Found: C, 61.70; H, 4.68; N, 15.40.
73

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
5.45 3-(6,7-DIMETHOXY-2-METHYL-4-0X0-4H-QUINTAZOLIN-3-YL)-
PIPERIDINE-2,6-DIONE
\o
o o
N 0
To a stirred mixture of 2-amino-4,5-dimethoxybenzoic acid (5.0 g, 25 mmol) and

imidazole (2.1 g, 30 mmol) in acetonitrile (50 mL), was added acetyl chloride
(2.2 mL, 30 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (4.2 g, 25 mmol),
imidazole (3.8 g, 56
mmol) and triphenyl phosphite (7.3 mL, 28 mmol) and heated to reflux for 22
hours. The
suspension was filtered and washed with acetonitrile (50 mL) and water (2 X 50
mL) to give a solid.
The solid was stirred in sodium hydrogen carbonate (sat, 50 mL), and water (50
mL) for 1 hour.
The suspension was filtered and washed with water (2 X 50 mL) and ethyl
acetate (30 mL) to give
3-(6,7-dimethoxy-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione as a
white solid (5.7 g,
68% yield): HPLC: Waters Symmetry C18, 51.tm, 3.9 x 150 mm, 1 mL/min, 240 nm,
20/80
CH3CN/0.1% H3PO4, 3.26 min (99.8 %); mp: 325 C (decomp); 1H NMR (DMSO-d6) 8
2.15-2.19
(m, 1H, CHH), 2.56-2.88 (m, 6H, CH3, CH2, CHH), 3.85 (s, 311, CH3), 3.90 (s,
3H, CH3), 5.22 (dd, J
= 5, 11 Hz, 1H, NCH), 7.09 (s, 1H, Ar), 7.35 (s, 1H, Ar), 10.99 (s, 1H, NH);
13C NMR (DMSO-d6) 8
21.12, 23.21, 30.62, 55.63, 55.97, 56.38, 104.98, 107.31, 113.27, 143.09,
148.40, 153.24, 154.83,
159.76, 169.61, 172.64; LCMS: MH = 332; Anal Calcd for C161112N305: C, 58.00;
H, 5.17; N, 12.68.
Found: C, 57.88; H, 5.06; N, 12.77.
5.46 3-16,8-DICHLOR0-2-METHYL-4-0X0-4H-QUINAZOLIN-3-YL)-
PIPERIDINE-2,6-DIONE
0 0
N¨tN0
CI N=c ____________________________
To a stirred mixture of 2-amino-3,5-dichlorobenzoic acid (5.0 g, 24 mmol) and
imidazole (1.9 g, 28 mmol) in acetonitrile (60 mL), was added acetyl chloride
(2.0 mL, 28 mmol) at
room temperature. The mixture was stirred at room temperature overnight. To
the mixture, was
added 3-amino-piperidine-2,6-dione hydrogen chloride (3.9 g, 24 mmol),
imidazole (3.5 g, 52
mmol) and triphenyl phosphite (6.8 mL, 26 mmol) and heated to reflux for 22
hours. The
suspension was filtered and washed with acetonitrile (30 mL), water (2 X 30
mL), and ethyl acetate
(30 mL) to give 3-(6,8-dichloro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-
2,6-dione as a
white solid (4.65 g, 58% yield): HPLC: Waters Symmetry Cig, 51.tm, 3.9 x 150
mm, 1 mL/min, 240
nm, 40/60 CH3CN/0.1% H3PO4, 4.78 min (100 %); mp: 238-240 C; IH NMR (DMSO-d6)
8 2.15-
2.22 (m, 111, CHH), 2.55-2.69 (m, 5H, CH3, 2CHH), 2.78-2.91 (m, 1H, CHIT]),
5.33 (dd, J = 6, 11
74

CA 02704710 2015-03-19
53686-95
Hz, 1H, NCR), 7.96 (d, J = 2 Hz, 1F1, Ar), 8.15 (d, J = 2 Hz, 1H, Ar),
11.09(s, 1H, NH); I3C NMR
(DMSO-d6) 8 20.63, 23.85, 30.54, 56.92, 122.55, 24.24, 130.51, 131.72, 134.38,
142.25, 156.80,
159.07, 169.12, 172.53; LCMS: =
340,342; Anal Calcd for C14H11N303C12: C, 49.43; H, 3.26;
N, 12.35; Cl, 20.84. Found: C, 49.21; H, 3.11; N, 12.30; Cl, 19.43.
5.47 3-(2-METHYL-4-0X0-411-BENZOIGIOUJNAZOLIN-3-YL)-PIPERIDINE-
2 6-DIONE
=0 0
11
To a stirred mixture of 3-amino-2-naphtholic acid (5.4 g, 29 mmol) and
imidazole
(2 g, 29 mmol) in acetonitrile (60 mL), was added acetyl chloride (2.1 mL, 29
mmol) at room
temperature. The mixture was stirred at room temperature overnight. To the
mixture, was added 3-
amino-piperidine-2,6-dione hydrogen chloride (4 g, 25 mmol), imidazole (3.7 g,
54 mmol) and
triphenyl phosphite (7.1 mL, 27 mmol) and heated to reflux for 22 hours. The
suspension was
filtered and washed with acetonitrile (30 mL), water (2 X 30 mL), and ethyl
acetate (30 mL) to give
3-(2-methy1-4-oxo-4H-benzo[g]quinazolin-3-yI)-piperidine-2,6-dione as a pale
white solid (6.3 g,
79% yield): HPLC: Waters Symmetry C18, 5 m, 3.9 x 150 mm, I mL/min, 240 nm,
30/70
CH3CN/0.1% H3PO4, 4.59 min (99.7 %); mp: 307 C (decomp); Ill NMR (DMSO-d6)
2.17-2.26
(m, 1H, CHH), 2.60-2.94 (m, 6H, CH3, CH2, CHH), 5.29 (dd, J = 5, 11 Hz, 1H,
NCR), 7.55-7.60 (m,
1H, Ar), 7.64-7.69 (m, 1H, Ar), 8.09 (d, J = 8 Hz, 1H, Ar), 8.18-8.20 (m, 2H,
Ar), 8.75 (s, 111, Ar),
11.06 (s, IH, Nil); 13C NMR (DMSO-d6) 8 21.16, 23.60, 30.71, 56.45, 119.52,
123.86, 126.25,
127.47, 127.77, 128.58, 129.24, 129.53, 136.26, 142.20, 153.87, 160.97,
169.70, 172.68; LCMS:
MH = 322; Anal Calcd for C18H1sN303 + 0.1 H20: C, 66.91; H, 4.74; N, 13.00.
Found: C, 66.78; H,
4.76;N, 12.95.
5.48 ASSAYS
= 5.48.1 TNFa Inhibition Assay in PMBC
Peripheral blood mononuclear cells (PBMC) from normal donors are obtained by
TM
Ficoll Hypaque (Pharmacia,Piseataway, NJ, USA) density centrifugation. Cells
are cultured in
RPMI 1640 (Life Technologies, Grand Island, NY, USA) supplemented with 10%
AB+human
serum (Gemini Bio-products, Woodland, CA, USA), 2 mM L-glutamine, 100 U/ml
penicillin, and
100 g/m1 streptomycin (Life Technologies).
TM
PBMC (2 x 105 cells) are plated in 96-well flat-bottom Costar tissue culture
plates
,I4?
(Corning, NY, USA) in triplicate. Cells are stimulated with LPS (from
Salmonella abortus equi,
Sigma cat.no. L-1887, St.Louis, MO, USA) at I ng/ml final in the absence or
presence of
compounds. Compounds provided herein are dissolved in DMSO (Sigma) and further
dilutions are
done in culture medium immediately before use. The final DMSO concentration in
all assays can be

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
about 0.25%. Compounds are added to cells 1 hour before LPS stimulation. Cells
are then
incubated for 18-20 hours at 37 C in 5 % CO2, and supernatants are then
collected, diluted with
culture medium and assayed for TNFa levels by ELISA (Endogen, Boston, MA,
USA). IC50s are
calculated using non-linear regression, sigmoidal dose-response, constraining
the top to 100% and
bottom to 0%, allowing variable slope (GraphPad Prism v3.02).
5.48.2 IL-2 and MILP-3a Production by T Cells
PBMC are depleted of adherent monocytes by placing 1 x 108 PBMC in 10 ml
complete medium (RPM! 1640 supplemented with 10% heat-inactivated fetal bovine
serum, 2 mM
L-glutamine, 100 U/ml penicillin, and 100 g/m1 streptomycin) per 10 cm tissue
culture dish, in
37 C, 5 % CO2 incubator for 30-60 minutes. The dish is rinsed with medium to
remove all non-
adherent PBMC. T cells are purified by negative selection using the following
antibody
(Pharmingen) and Dynabead (Dynal) mixture for every 1 x 108 non-adherent PBMC:
0.3 ml Sheep
anti-mouse IgG beads, 15 p.1 anti-CD16, 15 I anti-CD33, 15 1 anti-CD56, 0.23
ml anti-CD19
beads, 0.23 ml anti-HLA class II beads, and 56 i.tlanti-CD14 beads. The cells
and bead/antibody
mixture is rotated end-over-end for 30-60 minutes at 4 C. Purified T cells are
removed from beads
using a Dynal magnet. Typical yield is about 50% T cells, 87-95% CD3+ by flow
cytometry.
Tissue culture 96-well flat-bottom plates are coated with anti-CD3 antibody
OKT3
at 5 g/m1 in PBS, 100 I per well, incubated at 37 C for 3-6 hours, then
washed four times with
complete medium 100 l/well just before T cells are added. Compounds are
diluted to 20 times of
final in a round bottom tissue culture 96-well plate. Final concentrations are
about 10 M to about
0.00064 M. A 10 mM stock of compounds provided herein is diluted 1:50 in
complete for the first
20x dilution of 200 M in 2 % DMSO and serially diluted 1:5 into 2 % DMSO.
Compound is added
at 10 I per 200 1 culture, to give a final DMSO concentration of 0.1 %.
Cultures are incubated at
37 C, 5 % CO2 for 2-3 days, and supernatants analyzed for IL-2 and MIP-3a by
ELISA (R&D
Systems). IL-2 and MIP-3a levels are normalized to the amount produced in the
presence of an
amount of a compound provided herein, and EC50s calculated using non-linear
regression, sigmoidal
dose-response, constraining the top to 100 % and bottom to 0 %, allowing
variable slope (GraphPad
Prism v3.02).
5.48.3 Cell Proliferation Assay
Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the Deutsche Sammlung
von Mikroorganismen und Zellkulturen GmbH (Braunschweig, Germany). The cell
line KG-1 is
obtained from the American Type Culture Collection (Manassas, VA, USA). Cell
proliferation as
indicated by 3H-thymidine incorporation is measured in all cell lines as
follows.
Cells are plated in 96-well plates at 6000 cells per well in media. The cells
are pre-
treated with compounds at about 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0 M
in a final
concentration of about 0.25 % DMSO in triplicate at 37 C in a humidified
incubator at 5 % CO2 for
76

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
72 hours. One microcurie of3H-thymidine (Amersham) is then added to each well,
and cells are
incubated again at 37 C in a humidified incubator at 5 % CO2 for 6 hours. The
cells are harvested
onto UniFilter GF/C filter plates (Perkin Elmer) using a cell harvester
(Tomtec), and the plates are
allowed to dry overnight. Microscint 20 (Packard) (25 l/well) is added, and
plates are analyzed in
TopCount NXT (Packard). Each well is counted for one minute. Percent
inhibition of cell
proliferation is calculated by averaging all triplicates and normalizing to
the DMSO control (0 %
inhibition). Each compound is tested in each cell line in three separate
experiments. Final IC50s are
calculated using non-linear regression, sigmoidal dose-response, constraining
the top to 100 % and
bottom to 0 %, allowing variable slope. (GraphPad Prism v3.02).
5.48.4 Immunoprecipitation and Immunoblot
Namalwa cells are treated with DMSO or an amount of a compound provided
herein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for 30
minutes. Cell lysates
are prepared and either immunoprecipitated with Epo receptor Ab or separated
immediately by
SDS-PAGE. Immunoblots are probed with Akt, phospo-Akt (Ser473 or Thr308),
phospho-Gab I
(Y627), Gab 1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager
using ImageQuant
software (Molecular Dynamics).
5.48.5 Cell Cycle Analysis
Cells are treated with DMSO or an amount of a compound provided herein
overnight. Propidium iodide staining for cell cycle is performed using
CycleTEST PLUS (Becton
Dickinson) according to manufacturer's protocol. Following staining, cells are
analyzed by a
FACSCalibur flow cytometer using ModFit LT software (Becton Dickinson).
5.48.6 Apoptosis Analysis
Cells are treated with DMSO or an amount of a compound provided herein at
various time points, then washed with annexin-V wash buffer (BD Biosciences).
Cells are incubated
with annexin-V binding protein and propidium iodide (BD Biosciences) for 10
minutes. Samples
are analyzed using flow cytometry.
5.48.7 Luciferase Assay
Namalwa cells are transfected with 4 lag of AP1-luciferase (Stratagene) per 1
x 106
cells and 3 pi Lipofectamine 2000 (Invitrogen) reagent according to
manufacturer's instructions.
Six hours post-transfection, cells are treated with DMSO or an amount of a
compound provided
herein. Luciferase activity is assayed using luciferase lysis buffer and
substrate (Promega) and
measured using a luminometer (Turner Designs).
5.48.8 Anti-Proliferation Assay
77

CA 02704710 2010-03-23
WO 2009/042177 PCT/US2008/011124
Day 1: The cells are seeded to 96-well plate with 50u1/well in 10%FBS RPMI (w/
Glutamine, w/o pen-strip) for overnight. The following cells are used:
Colorectal cancer cell: Colo 205 3200cells/well; positive control irinotecan
Pancreatic cancer cell: BXPC-3 1200cells/well; positive control gemcitabine
Prostate cancer cell: PC3 1200cells/well; positive control docetaxel
Breast cancer cell: MDA-MB-231 2400ce11s/well; positive control paclitaxel
Day 2: The compounds are serially diluted from 0.00001 m-10 m (or
0.000001-1 M) with 50 111/well (of 2x) and added to the plates in duplicate
with relative positive
control. The plates were then incubated at 37 C for 72 hours.
Day 5: The results are detected by CellTiter Glo method. 100 p.1 /well of
CellTiter
Glo reagent is added to the plates and incubated for 10 minutes at room
temperature, and then
analyzed on the Top Count reader. The IC50 of each compound is typically based
on the result of
two or more individually experiments.
5.49 TNFa INHIBITION
Abilities of certain compounds for inhibiting TNFa were determined using
procedures substantially similar to those described in Section 5.48.1, above.
The tested compounds included: 3-(7-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-
piperidine-2,6-dione; 3-(2,7-dimethy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione; 3-(2,8-
dimethy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione; 3-(6,7-dimethoxy-2-
methy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione; 3-(7-fluoro-2-methy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-
2,6-dione; 3-(7-chloro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione; 3-(7-bromo-2-
methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione; 3-(8-bromo-2-methy1-4-
oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione; 3-(8-hydroxy-2-methy1-4-oxo-4H-
quinazolin-3-y1)-
piperidine-2,6-dione; 3-(2-methy1-4-oxo-8-trifluoromethy1-4H-quinazolin-3-y1)-
piperidine-2,6-
dione; heptanoic acid [3-(2,6-dioxo-piperidin-3-y1)-2-methyl-4-oxo-3,4-dihydro-
quinazolin-6-
ylmethy1]-amide; cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-y1)-2-
methyl-4-oxo-3,4-
dihydro-quinazolin-6-ylmethyl]-amide; 2-(4-chloro-pheny1)-N43-(2,6-dioxo-
piperidin-3-y1)-2-
methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-acetamide; 143-(2,6-dioxo-
piperidin-3-y1)-2-
methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea; 1-(4-chloro-
phenyl)-343-(2,6-
dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy1]-urea;
143-(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy1]-3-m-tolyl-
urea; 143-(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy1]-3-(4-
trifluoromethoxy-pheny1)-
urea; N43-(2,6-dioxo-piperidin-3-y1)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-
ylmethyl]-4-
trifluoromethyl-sulfanyl-benzamide; 1-(3-chloro-4-methyl-pheny1)-343-(2,6-
dioxo-piperidin-3-y1)-
2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea; 4-chloro-N13-(2,6-
dioxo-piperidin-3-y1)-
2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-benzamide; N13-(2,6-dioxo-
piperidin-3-y1)-2-
methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide; N-
[3-(2,6-dioxo-
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CA 02704710 2010-03-23
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piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy11-4-
trifluoromethoxy-benzamide;
3,4-dichloro-N43-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-
quinazolin-5-ylmethyl]-
benzamide; and N43-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-
quinazolin-6-
ylmethyl]-4-trifluoromethyl-benzamide. From the tests, it was determined that
IC50 values of the
tested compounds were in the range of 0.01 to 25 M.
5.50 IL-2 PRODUCTION
Abilities of certain compounds for stimulating the production of IL-2 were
determined using procedures substantially similar to those described in
Section 5.48.2, above.
The tested compounds included: 3-(6-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-
piperidine-2,6-dione; 3-(7-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-
2,6-dione; 3-(7-
fluoro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione; 3-(7-chloro-2-
methy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione; 3-(7-bromo-2-methy1-4-oxo-4H-quinazolin-
3-y1)-piperidine-
2,6-dione; 3-(6-hydroxy-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-
dione; 143-(2,6-dioxo-
piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethy1]-3-hexyl-
urea; and 14342,6-
dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-
trifluoromethoxy-
pheny1)-urea. From the tests, it was determined that EC50 values of the tested
compounds were in
the range of 0.1 to 3.511M.
5.51 CELL PROLIFERATION
Abilities of certain compounds for inhibiting proliferation of Namalwa AG4
cells
were determined using procedures substantially similar to those described in
Section 5.48.3, above.
The tested compounds included: 3-(6-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-
piperidine-2,6-dione; 3-(7-amino-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-
2,6-dione; 3-(7-
fluoro-2-methy1-4-oxo-4H-quinazolin-3-y1)-piperidine-2,6-dione; 3-(7-chloro-2-
methy1-4-oxo-4H-
quinazolin-3-y1)-piperidine-2,6-dione; 3-(7-bromo-2-methy1-4-oxo-4H-quinazolin-
3-y1)-piperidine-
2,6-dione; heptanoic acid [3-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4-
dihydro-quinazolin-6-
ylmethyl]-amide; 2-(4-chloro-pheny1)-N-P-(2,6-dioxo-piperidin-3-y1)-2-methyl-4-
oxo-3,4-dihydro-
quinazolin-6-ylmethyli-acetamide; 143-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-
oxo-3,4-dihydro-
quinazolin-6-ylmethy1]-3-hexyl-urea; 1-(4-chloro-pheny1)-343-(2,6-dioxo-
piperidin-3-y1)-2-methy1-
4-oxo-3,4-dihydro-quinazolin-6-ylmethylFurea; 143-(2,6-dioxo-piperidin-3-y1)-2-
methy1-4-oxo-
3,4-dihydro-quinazolin-6-ylmethy1]-3-m-tolyl-urea; 143-(2,6-dioxo-piperidin-3-
y1)-2-methy1-4-oxo-
3,4-dihydro-quinazolin-6-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea; N-[3-
(2,6-dioxo-piperid in-
3-y1)-2-methy1-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethyl-
sulfanyl-benzamide;
1-(3-chloro-4-methyl-pheny1)-3-[3-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-
3,4-dihydro-
quinazolin-6-ylmethy1]-urea; N-[3-(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-
3,4-dihydro-
quinazolin-6-ylmethyl]-3-trifluoromethyl-benzamide; N-[3-(2,6-dioxo-piperidin-
3-y1)-2-methy1-4-
oxo-3,4-dihydro-quinazolin-6-ylmethyl]-4-trifluoromethoxy-benzamide; 3,4-
dichloro-N43-(2,6-
dioxo-piperidin-3-y1)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-
ylmethylFbenzamide; and N-[3-
79

CA 02704710 2015-03-19
53686-95
(2,6-dioxo-piperidin-3-y1)-2-methy1-4-oxo-3,4odihydro-quinazolin-6-ylmethyl]-4-
trifluoromethyl-
benzamide. From the tests, it was determined that IC50 values of the tested
compounds were in the
range of 0.01 to 5.5 M.
The embodiments of the invention described above are intended to be merely
exemplary, and those skilled in the art will recognize, or will be able to
ascertain using no more than
routine experimentation, numerous equivalents of specific compounds,
materials, and procedures.
All such equivalents are considered to be within the scope of the invention
and are encompassed by
the appended claims.
Citation or identification of any reference in this application
is not an admission that such reference is available as prior art to this
invention. The full scope of
the invention is better understood with reference to the appended claims.

Representative Drawing